cord-000018-amvlm09p	2008	
cord-000083-3p81yr4n	2009	R. China Background: The objective of this study was to evaluate the early virologic response for prediction of achievement of HBeAg seroconversion and hepatitis B virus (HBV) DNA negativity after two years of lamivudine treatment in chronic hepatitis B (CHB) patients. Methods: A total of 620 patients who tested positive for hepatitis B surface antigen and were referred to Chiba University Hospital between February 1985 and March 2008 were included in the study, and their following characteristics were analyzed: age, gender, the status of HBeAg, ALT, HBV-DNA level, and PLT. Methods: A total of 60 patients with chronic hepatitis B, 32 (53.3%) were HBeAg positive (group A) while 28(46.7%) were HBeAg negative (group B) were included in this study after meeting the following criteria: age 18 to 60 years, HBsAg positive for more than 6 months, serum HBV-DNA was >5 log(10) copies/mL and ALT more than two times the upper normal limit.
cord-000103-3zh8jmc2	2009	
cord-000104-3b8b8p61	2009	
cord-000125-uvf5qzfd	2009	The interaction between a PAMP and a PRR triggers activation of the interferon (IFN) pathway in mammalian cells, which significantly changes the gene-expression profile in the cells and contributes to the well-documented off-target effect of RNAi. IFN induction is especially problematic in antiviral studies employing RNAi, where the antiviral effect of IFN must be distinguished from that of RNAi. Typical IFN-inducing structure patterns include dsRNA of certain length, single-stranded RNA (ssRNA) containing 5 0 -triphosphates (5 0 -ppp), the dsRNA analogue polyinosinic-polycytidylic acid (poly I:C), and certain dsDNA molecules. Mammalian expression plasmids encoding each of these proteins, as well as the dominant negative (DN) mutants of RIG-I and MDA5, were transfected into 293FT cells with shRNAs and an IFN-b promoter reporter construct.
cord-000164-094d0rn6	2010	
cord-000403-vzbh457k	2011	
cord-000409-lpf9lpky	2011	Fluorescence double-staining revealed that FGL2 and PD-1 were not co-expressed on the same cells, while quantitative RT-PCR demonstrated that higher levels of IFN-γ and TNF-α mRNA transcription occurred in PD-1-deficient mice in response to MHV-3 infection. In all, these results demonstrated that PD-1 deficiency led to enhanced pathological damage by MHV-3 in the liver, spleen, lymph node and thymus, where higher levels of PD-1-positive cells were found after infection. Results showed that the expression of FGL2 was principally associated with CD31-positive endothelial cells, CD68-positive macrophages and CD11c-positive DCs. Surprisingly, significantly higher levels of FGL2 were observed after infection in all of PD-1-deficient organs, including the liver, thymus, spleen, lymph nodes, and serum than that in those from WT littermates. However, the number of Foxp3-positive cells in the liver, spleen, lymph node or thymus was not significantly different between PD-1-deficient mice and their WT littermates after 72 h of MHV-3 infection (Fig. S3) .
cord-000478-88wo4xen	2011	Intranasal administration of DEF201 24 h prior to challenge with Pichindé virus (PICV) was highly effective at protecting animals from mortality and preventing viral replication and liver-associated disease. Interestingly, the 10 7 and 10 8 pfu DEF201 groups presented with little to no day-7 virus burden in the serum, liver, or spleen, while the 10 6 group developed viral titers that were comparable to the rAd EV and placebo controls ( Figure 2B-D) . This may not be the case with hamsters treated with DEF201 24 h prior to challenge since most had no detectable virus titers in spleen, liver, or serum on day 7 of PICV infection ( Figure 2B-D) . Animals were treated i.n. with a single dose 10 8 pfu of DEF201, the rAd EV control virus, or PBS placebo 7 or 14 days prior to PICV infection.
cord-000554-p4ufea6x	2012	title: Distinct Regulation of Host Responses by ERK and JNK MAP Kinases in Swine Macrophages Infected with Pandemic (H1N1) 2009 Influenza Virus We have also observed cross-talk between MAP kinase and NFkB pathways, and our data indicate that MAP kinase ERK1/2 and JNK1/2 may impact the activation of NFkB through the induction of RIG-1, leading to IFN-b induction in H1N1pdm-infected swine macrophages. To understand the mechanism of proinflammatory cytokine and TNF family ligand induction in H1N1pdm-infected swine macrophages, we investigated how MAP kinases were activated and whether their signaling pathways were involved in the regulation of various cytokines and TNF family ligands in pig immune cells. To evaluate the role of MAP kinases in the regulation of proinflammatory cytokine responses in H1N1pdm-infected swine macrophages, we pre-treated 3D/4 cells with specific inhibitors for ERK1/2, p38, and JNK1/2 1 hr prior to infection.
cord-000660-tsvzg0ax	2012	Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. In contrast, in acute infection by viruses that cause severe pathogenesis and death within a few days after infection, protection is primarily provided by the intrinsic antiviral actions of IFN-induced proteins encoded by the hundreds of IFN-stimulated genes (ISGs) [10] [11] [12] , several of which often contribute to the overall effect of IFN against a given virus. From the above observations, we conclude that after intranasal infection by VSV, Ifit2 protects mice from neuropathogenesis by suppressing replication or spread of the virus in brain neurons. In the complete absence of type I IFN action in the IFNAR 2/2 mice, intranasally infected VSV replicated vigorously not only in brains, but also in livers and lungs ( Figure 7A-C) .
cord-000725-rafwlw0t	2012	Experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice expressing signaling defective dominant-negative interferon gamma (IFN-γ) receptors on astrocytes to determine the influence of inflammation on astrocyte activity. Inhibition of IFN-γ signaling to astrocytes did not influence disease incidence, onset, initial progression of symptoms, blood brain barrier (BBB) integrity or the composition of the acute CNS inflammatory response. GFAPcR1D and wt mice were compared at the peak of acute disease to determine if IFN-c signaling altered astrocyte activation or CNS inflammation. Despite elevated demyelination and axonal loss in the absence of IFN-c signaling to astrocytes, spinal cords showed no evidence of differential astrocyte activation by either immunohistochemistry (Fig. 4 ), or differences in GFAP mRNA expression during the peak of acute disease (Fig. 5 ). Although demyelination was increased in the CNS of GFAPcR1D mice, the extent of astrocyte activation associated with spinal cord white matter lesions was similar in both groups ( Fig. 6 ; ,60 GFAP + cells/mm 2 ).
cord-001109-xs7df6a7	2013	
cord-001124-qcjbtflt	2013	
cord-001236-cgiok0ce	2014	
cord-001273-plz1ja2e	2014	
cord-001359-c1uom5f7	2014	
cord-001397-nrq4ncdf	2014	Avenues for additional studies include determining if the multifunctional flavivirus protein NS5 has a role in viral persistence, the development of relevant animal models of viral persistence as well as investigating the host responses that allow vector borne flavivirus replication without detrimental effects on infected cells. The SL1 structure is essential for viral replication and acts as a promoter which is targeted initially by NS5 and then delivered to the 3 0 end via cyclization (Filomatori et al., 2006; Zhang et al., 2008; Lodeiro et al., 2009) Although there is low nucleotide conservation between flaviviruses and different CS homology (Hahn et al., 1987) , the 5 0 UTRs of TBFVs share the same genomic organization as the MBFVs (Kofler et al., 2006) Structural proteins Capsid (C) 11 kDa, 114 aa Cytosol/nucleus The capsid protein is a dimeric alpha-helical (Jones et al., 2003) protein and assembles into an icosahedral structure, measuring 30 nm in diameter, which initiates encapsidation of the associated genomic RNA in virus-induced membrane invaginations of the ER (Welsch et al., 2009 ).
cord-001515-x11t9pbv	2014	Several innovative approaches combining antiviral treatments using nucleos(t)ide analogues, with prime-boost vaccination using DNA vaccines, new hepadnaviral antigens or recombinant adenoviral vectors were tested in the woodchuck model. The woodchuck (Marmota monax) and its HBV-like woodchuck hepatitis virus are a useful preclinical animal model for developing new therapeutic approaches in chronic hepadnaviral infections. The woodchuck (Marmota monax) and its HBV-like woodchuck hepatitis virus are a useful preclinical animal model for developing new therapeutic approaches in chronic hepadnaviral infections. The results of these studies clearly showed that combination of antiviral treatment and vaccination is more effective in inducing virus-specific T cell responses than therapeutic vaccination alone. The DNA prime-AdV boost immunization strategy was further used as a therapeutic vaccine against chronic WHV infection in combination with antiviral treatment with ETV. T-helper cell response to woodchuck hepatitis virus antigens after therapeutic vaccination of chronically-infected animals treated with lamivudine
cord-001542-f089bs8r	2014	
cord-001546-ndz3oarf	2015	Importantly, proinflammatory cytokine/chemokine expression was much higher in WT mice without VLPs than mice treated with VLPs. In EBOV infected Ifnar(-/-) mice, however, uninhibited viral replication and elevated proinflammatory factor expression ensued, irrespective of VLP treatment, supporting the view that type I IFN signaling helps to limit viral replication and attenuate inflammatory responses. Further analyses showed that VLP protection requires the transcription factor, IRF8 known to amplify type I IFN signaling in dendritic cells and macrophages, the probable sites of initial EBOV infection. The aim of this study was to further investigate molecular bases of postexposure protection by VLPs. Based on our previous report that VLPs stimulate type I IFN expression in DCs and macrophages, in vitro, we focused on the role of type I IFN signaling, and found that post-exposure VLP treatment leads to accelerated activation of IFN signaling, resulting in early induction of ISGs. Significantly, VLP stimulated ISG induction coincided with the attenuation of proinflammatory cytokine surge in EBOV infected mice.
cord-001676-68y733y3	2015	
cord-001808-47496o0e	2015	Based on previous studies identifying a causative role for anti-cytokine autoantibodies in patients with opportunistic infections, we explored this possibility in PHN. CONCLUSIONS: These results suggest the possibility that sporadic anti-cytokine autoantibodies in some subjects may cause an autoimmune immunodeficiency syndrome leading to uncontrolled VZV reactivation, nerve damage and subsequent PHN. High levels of neutralizing anti-IFN-γ autoantibodies were also detected in patients with disseminated nontuberculous mycobacteria and other opportunistic infections, including both with localized and disseminated VZV reactivation [14, 15] . The finding that several patients each harbored single, neutralizing autoantibodies against interferon-α, GM-CSF or IL-6 suggests that anti-cytokine immunodeficiency may contribute to development of PHN. Particularly relevant was the finding of six PHN patients (one against anti-IFN-α, three against IFN-γ, one against GM-CSF, and one against IL-6) with high levels of autoantibodies greater than 100,000 LU that might have potential neutralizing activity against the target (Fig. 1) .
cord-001834-6xf4o3oy	2015	
cord-001848-idmj2d7p	2015	We performed live confocal imaging, cell death and proliferation assays, mRNA expression profiling, protein detection, and antibody blocking assays using transient and inducible stable in vitro systems. Previously, we showed that transient transfection of an expression construct that generates IFN-l4 protein induced interferon signaling, with activation of interferon-stimulated genes (ISGs) and generation of antiviral response in HepG2, a human hepatoma cell line (Prokunina-Olsson and others 2013). The stable HepG2-ISRE-Luc cells were transfected with corresponding constructs in 96-well plates; untransfected cells were treated with human recombinant interferons-IFNa (2 ng/mL; PBL Assay Science) or custom IFN-l3 (10 ng/ mL). Previously, by performing Western blot analysis, we were unable to detect IFN-l4 in culture media of HepG2 cells transiently transfected with an IFN-l4-producing construct, even though this transfection resulted in strong activation of interferon signaling (Prokunina-Olsson and others 2013). IFN-l4 was detectable in culture media of IFNL4-transfected PHHs and HepG2 cells, but not in corresponding Halo-transfected cells (Fig. 2B) .
cord-001868-utsvsja0	2015	
cord-001901-2s6hpakk	2016	
cord-001964-iy6qzq58	2016	
cord-002021-67ao8chx	2016	
cord-002068-e071ciil	2016	
cord-002079-jne14jqf	2016	
cord-002201-pnw5ytj4	2016	
cord-002238-fyztb8d9	2016	
cord-002248-92pzqj35	2016	
cord-002630-5616n73p	2017	We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumab, ocrelizumab, alemtuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS. Based on Phase III human clinical trials in patients with RRMS (TRANSFORMS, FREEDOMS and FREEDOMS II), fingolimod was more effective compared to first line treatment IFNβ-1a and placebo, in reducing the frequency of flare-ups (clinical exacerbations), disability progression, MRI outcome measures, including brain volume loss and was associated with clearly identified adverse events [103, 136, 137] . Citrullination of linear and cyclic altered peptide ligands from myelin basic protein (mbp(87-99)) epitope elicits a th1 polarized response by t cells isolated from multiple sclerosis patients: Implications in triggering disease
cord-002670-rjrw875d	2017	
cord-002844-jv42o789	2018	
cord-002937-7xauocti	2018	
cord-003130-p2h8p5bm	2018	
cord-003239-nph2ezii	2018	
cord-003261-fz8ucwwm	2018	
cord-003300-994731g9	2018	
cord-003315-r1wkx0ml	2018	
cord-003382-v3w1wi5c	2018	
cord-003492-rodqdtfj	2019	
cord-003514-yyzbv7ys	2019	The transcriptional profiling using RNA-seq and subsequent bioinformatics analysis (gene ontology, differential expressed genes, and KEGGs analysis) of the bursa of Fabricious and the thymus demonstrated an upregulation of crucial immune genes (viperin, IKKB, CCL5, IL1β, and AP1) as well as the antiviral signaling pathways. Although CEF do not possess receptors for IFN-λ, slight temporal expression of DEGs in response to chIFN-λ treatment signifies its antiviral potential in primary cells. Furthermore, studies have also revealed that a high degree of cell type specificity in receptor-ligand interactions make avian IFNs distinct from mammalian IFNs. Recently, it has been established that chicken IFN-λ inhibits low pathogenic influenza virus replication in CEFs; however, as compared to chIFN-γ and chIFN-β, higher doses are required to induce ISGs and maintain the strong antiviral state in the cells [14] . Our data suggest that significant antiviral, cell cycle regulators, and biologically active genes are expressed in response to administered chicken IFN.
cord-003614-63rzzos3	2019	
cord-003855-so8xl199	2019	The bat innate immune response appears to be ''pre-activated'' with higher basal levels of type I interferon expression, in contrast to humans, who are very quick responders to viral infections, but require a lot more dampening of their immune signals afterwards to get back to basal levels. demonstrated that bats'' response to stress in form of viral infections is more targeted and thus potentially more effective by numerous adaptions and modifications of the innate immune system. In the ''Pathogenesis and Prevention of Infection'' session, Rosa Coldbeck-Shackley working with Michael Beard at the University of Adelaide, Australia, and also colleagues at the Hudson Institute, presented findings on the importance of interferon-epsilon (IFN-ɛ) in the innate immune response to ZIKV infection. Also in the ''Pathogenesis and Prevention of Infection'' session, Allison Abendroth (University of Sydney) presented ''Disarming the killer: targeting of natural killer cells by varicella zoster virus''.
cord-004334-y1fcw1dj	2019	
cord-004341-co9s26x1	2020	Pre-challenge immune responses For Trial I (i.e., safety study), the T cell response was evaluated at 6 weeks post-vaccination by performing IFN-γ ELISA on spleen derived lymphocytes (described in Methods) (Supplemental Fig. 1 ). Post-challenge immune responses To evaluate T cell response in Trial I/safety study IFN-γ ELISA was performed and result of which depicted no significant differences in IFN-γ levels among the groups (Supplemental Fig. 2b ) while at 12 weeks post challenge Mycopar and PAN-lysate vaccinated animals showed significantly higher IFN-γ levels as compared with control animals given PBS (Supplemental Fig. 2c ). At 12 WPC, multiparametric flow cytometry analysis indicated that mice immunized with PAN-Cf elicited a significantly higher percent of antigen specific double cytokine (IFN-γ, TNF-α + ) and single cytokine (IFN-γ) producing CD8 + T cells compared with non-vaccinated and Mycopar® vaccinated mice (Fig. 4 ).
cord-004400-li1sc47z	2020	
cord-004675-n8mlxe7p	2019	However, the mean infusion rate per site was similar between patients aged <18 years ( XMEN disease (X-linked Immunodeficency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a primary immune deficiency caused by mutations in MAGT1 and characterized by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia. We present the case of a 1-year old Hispanic infant with a pathogenic variant in MAGT1 gene that clinically manifested with early Pneumocystis jirovecii and cytomegalovirus (CMV) interstitial pneumonia, and EBV chronic infection with good response to intravenous immunoglobulins supplementation without hematopoietic stem cell transplantation or gene therapy. Chief, Laboratory of Clinical Immunology and Microbiology, IDGS, DIR, NIAID, NIH, Bethesda, MD, USA Hypomorphic Recombination Activating Gene 1 (RAG1) mutations result in residual T-and B-cell development in both humans and mice and have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI).
cord-004685-qote5nx2	1994	The data indicate, among the mechanisms of resistance against the virus infection, a role of IFN gamma macrophage-activation and of antibodies against MHV3 which may delay the mean survival time in susceptible animals. The virus replication in target cells, the antiviral state induced by interferon (IFN) and the expression of a monokine with procoagulant activity (PCA) have been implicated in the resistance/susceptibility of the genetic homogeneous or heterogeneous mouse populations to the MHV3 infection [t, 2, 4, 7, 17, 18, 23, 243 . For the study of the individual correlation between in vivo resistance and in vitro inhibition of virus replication by IFN gamma, peritoneal macrophages from Hm, Lm and F 2 segregants were collected without sacrificing the animals, which were infected with MHV3 a week later. This brings further support to our previous suggestion that one of the main mechanisms involved in the resistance of mice to the MHV3 infection is based on the ability of their macrophages to restrict the virus replication upon IFN gamma activation [10 13, 153 .
cord-005077-ejgzfzd2	2004	
cord-005119-vsvc437g	1996	
cord-005393-rhji4io9	1997	
cord-005595-vzkcin1l	1986	
cord-005664-n4xv247l	2002	In the tracheal aspirates the immune balance was characterized by a proinflammatory response pattern, with a significant increase in TNF-α and IL-6 concentrations; concentrations of anti-inflammatory mediators remained very low. Conclusions: Two hours of servoflurane and mechanical ventilation using a tidal volume of 10 ml/kg is associated with remarkable changes in the immune response in infants without preexisting lung pathology undergoing cardiac catheterization. Conclusions: Two hours of servoflurane and mechanical ventilation using a tidal volume of 10 ml/kg is associated with remarkable changes in the immune response in infants without preexisting lung pathology undergoing cardiac catheterization. The major finding of the present study is that exposing infants with normal lung function to 2 h of volatile anesthetics, mechanical ventilation, and cardiac catheterization is associated with remarkable changes in immune responses. We observed a proinflammatory response in the lungs with a significant increase in TNF-α, while antiinflammatory cytokine concentrations in tracheal aspirates remained virtually unchanged, just above the detection level.
cord-005953-5z89yeb6	2008	Die anderen beiden Gruppen zeigten zwar in Hinblick auf die Wandstärken einen positiven Effekt, hinsichtlich der Herzfunktion konnten sie jedoch bei bereits deutlich erniedrigten Funktionswerten zum Baseline-Zeitpunkt lediglich stabilisiert werden (Reduktion der Wandstärke nach 3 Jahren ERT: Gruppe wenig Fibrose= 10 mm; Gruppe viel Fibrose= 12 mm) Schlussfolgerung: Die Enzymersatztherapie ist eine effektive Langzeitbehandlung bei Patienten mit Fabry Kardiomyopathie. Der Einfluss der sauren Sphingomyelinase auf die Expression von Matrix-Metalloproteinase-1 in intestinalen Epithelzellen und Fibroblasten Background: The calcineurin (Cn)/NF-AT signaling cascade takes a crucial role during T-cell activation and the development of myocardial hypertrophy. Effective and safe reduction of blood pressue by the combination of amlodipine 5/valsartan 160 mg in patients with hypertension and metabolic risk factors not controlled by amlodipine 5 mg or felodipine 5 mga subanalysis of the express-m trial Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia and frequently occurs in patients with coronary heart disease.
cord-006444-eq56zhtd	1993	The results from ongoing preclinical studies continue to confirm the broad spectrum of biological activities possessed by rhiL-1 1 in vitro and suggest this cytokine may be an effective agent in the treatment of myelosuppression associated with cancer chemotherapy and bone marrow transplantation. We performed a phase H trial to assess the ability of G-CSF -mobilized PBPC to rapidly and completely restore hemopeiesis after high dose chemotherapy in the absence of bone marrow infusions, with selection for PBPC-only infusions based on yield of granulocyte -macrophage colony -forming cells (GM-CFC) after G-CSF treatment. Our approach for high-dose (HD) chemotherapy is to first treat patients eligible for dose intensification with a standard dose chemotherapy (VIP: VP26 = etoposide: 500 mg/m 2, ifosfamide: 4 g/m 2, cis-platinum: 50 mg/m 2) followed by the application of colony stimulating factors (G-CSF, GM-CSF or IL-3 + GM-CSF) in order to combine a regimen with broad anti-tumor activity with the recruitment of peripheral blood progenitor cells (PBPCs).
cord-006828-i88on326	2013	
cord-007013-tlvgyzft	2018	Previously, we used the ferret model to demonstrate that viral interference can occur following infection with human influenza A and B viruses and will prevent, delay, or limit subsequent infection with an influenza virus of a different type, subtype, or lineage [10, 11] . The peak of hRSV shedding was delayed in ferrets infected with A(H1N1)pdm09 followed by hRSV as compared to control animals infected with hRSV alone (median, 8 vs 6 days; P = .0091 by the Mann-Whitney test; Figure 2Ci ). The median duration of A(H1N1)pdm09 shedding was increased in ferrets infected with hRSV followed by A(H1N1)pdm09 as compared to control animals infected with A(H1N1)pdm09 alone (8 vs 7 days; P = .0196 by the Mann-Whitney test; Figure 2Civ ). Notably, increased expression of inflammatory mediators following infection with influenza virus as compared to hRSV has been observed in studies assessing human clinical samples and in vitro airway epithelial cell cultures [36] [37] [38] [39] .
cord-007382-5kb16qb7	2016	
cord-007417-az8xd66p	2008	
cord-007621-rapinodd	2002	
cord-007646-yh8zi1ee	2002	The effect of recombinant human interferon-alpha (rHuIFN-α) in vitro and in vivo on mitogen-induced lymphocyte blastogenesis was evaluated in specific-pathogen-free cats. Pre-incubation of isolated feline peripheral blood lymphocytes (PBL) in vitro with either 104 or 103 International Units (U) of rHuIFN-o~ for 24 h significantly suppressed (P < 0.001 and 0.01, respectively) blastogenic responses to the phytomitogens concanavalin A (Con A) and pokeweed mitogen (PWM). Pre-incubation of isolated feline peripheral blood lymphocytes (PBL) in vitro with either 104 or 103 International Units (U) of rHuIFN-o~ for 24 h significantly suppressed (P < 0.001 and 0.01, respectively) blastogenic responses to the phytomitogens concanavalin A (Con A) and pokeweed mitogen (PWM). Although the suppressive mechanism (s) associated with rHuIFN-c~ on DNA synthesis and lymphocyte blastogenesis were not investigated in our study, it is possible that high doses of IFN in vitro enhanced lectin-binding on lymphocytes and stimulated suppressor cell activities.
cord-007654-lchdm4xr	2002	
cord-007664-c5snhymz	2002	To gain an insight into the regulation of HLA in the different cell types in the CNS and to compare it to that observed in the endocrine organs, we have studied the effect of the lympho/monokines interferon (IFN)-α and -γ, tumour necrosis factor (TNF)-α, and interleukin (IL)-2 and other agents on this aspect of the biology of human fetal brain cells in culture. It has previously been reported that primary cultures of human fetal brain tissue can be a useful substrate for studying the expression of cell type-specific antigens, e.g. gangliosides, tetanus toxin receptors (Dickson et al., 1982 (Dickson et al., , 1985 , and the present data confirm that they can also be successfully employed to investigate the expression and modulation of HLA molecules.
cord-007689-0vpp3xdl	2007	
cord-007696-83v9yfa6	2005	Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease limited to the lungs and associated with the histologic appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy. Factors that predict poor outcome include older age, male gender, severe dyspnea, history of cigarette smoking, severe loss of lung function, appearance and severity of fibrosis on radiological studies, lack of response to therapy, and prominent fibroblastic foci on histopathologic evaluation. With greater comprehension of the clinical relevance of the different histopathological subgroups that make up the idiopathic interstitial pneumonias, the term idiopathic pulmonary fibrosis (IPF) is now reserved to patients with idiopathic usual interstitial pneumonia (UIP) on surgical lung biopsy. Tang In a recent study, human T-lymphtropic virus type I (HTVL-I) positive IPF patients had more affected lung parenchyma, demonstrated traction bronchiectasis with honeycomb change, and exhibited increased levels of specific cytokines that correlated with activated T-cells in the bronchoalveolar lavage fluid (BALF).
cord-007783-z1vv63u2	2012	
cord-007796-zggk0x2q	2005	In respect to the role of viruses in the pathogenesis of acute and chronic airway disease in children, it is of utmost importance that we gain a proper understanding of the underlying mechanisms involved in order to design effective therapeutic and preventive strategies. Epithelial cells are key regulators of the innate immune response against viral infections (Garofalo and Haeberle, 2000) , producing a number of inflammatory mediators in response to RSV infection. In summary, in RSV lower respiratory tract infections, cytotoxic CD8Ï© T-cells are involved in viral clearance while the humoral response is required for the protection against reinfection. The innate immune defense to viral respiratory tract infections consists of the mucosal layer, type 1 interferons, activated phagocytes, and NK-cells. A key question is whether the association with the development of asthma is merely an expression of increased susceptibility to both asthma and RSV-induced lower respiratory tract infections or whether true causality is involved.
cord-007890-bie1veti	2002	Effects of Interferon alpha plus ribavirine therapy on frequencies of HCV, HIV and CMV specific CD4-T-cell responses in peripheral blood of HIV/HCV coinfected patients after 6 months of treatment SoA9.5 Methods: Two groups of patients with chronic HCV infection were studied: 26 HIV coinfected progressors with antiretroviral therapy and 13 HIV-negative controls. In order to assess the local temporal trend of antibiotic sensitivity of the most common urinary tract bacterial pathogen, all urine-cultured Escherichia coli isolates were reviewed as to susceptibility profile, and specimen source (community-versus hospital-acquired infection). Methods: A total of 87 penicillin resistant clinical strains isolated from patients at Hacettepe Children''s Hospital, Ankara, Turkey between 1999 and 2001 were tested for their in vitro susceptibility to various antibiotics that are commonly used in the treatment of respiratory tract infections.
cord-008761-b36x05fn	2012	Possessing satisfactory answers to these questions is essential, not only to understand the natural role of the interferon system in virus disease but also to assess possible applications in medicine, in particular the use of interferons or interferoninducing substances as antiviral drugs. Interferon prepared from mouse cell lines infected with Newcastle disease virus is a mixture of a and B (6) . The main difference between these products and their natural-source-derived counterparts is that they contain only a single subtype, namely a2'' While it is known that different subtypes of HuIFN-~ may differ in their antiviral potency depending on the cells on which they are tested, it is not yet known whether this has any repercussion for the clinical effects. Although these side-chains do not playa significant role in the effects of the IFN-S on cells, the pharmacokinetic behavior of this rDd-IFN-S was found to be rather different from that of natural fibroblast-derived interferon (8) .
cord-008821-rxzgfk1k	2011	Abbreviations; MHV3 = mouse hepatitis virus 3; IFN = interferon; Fes = fetal calf serum; PFU = plaque-forming units; ip = intraperitoneally; Ab = antibodies; PBS = phosphate buffer solution against our strain of MHV3 is acquired after immunization and the mechanism involved is dependent on the IFN -y synthesis and the macrophage sensitivity to IFN-y (9). Although, in view of the crucial regulatory function of CD4 cells and the important role of CDS cells as cytotoxic effector cells during a virusspecific immune response, the results cannot unequivocally exclude the interpretation that susceptibility of the immunosuppressed animals may be due to the absence of proper immune effector mechanisms, the lack of clearance of the virus in the peritoneum and liver of AI] treated and infected mice (Figure 1) , which leads to high rates of mortality (Table 1) , may be attributed to the lack of IFN-y in the serum or peritoneal exudate of them (Fig. 3) , which has been shown in vitro to be effective to restrict the MHV3 growth in target cells such as macrophages (6, 7, 9) .
cord-009567-osstpum6	2008	Introduction: Previously, it has been demonstrated that FOXP3, a gene required for the development and function of regulatory T cells, was highly expressed in the graft during cardiac rejection, suggesting infiltration of regulatory T cells in the transplanted organ during an allogeneic response. Efficacy and safety parameters assessed at follow-up included: acute rejection; patient and graft survival; renal function, vital signs, basic lab results and immunosuppressive regimen for the patients 10 years after completion of the original study. We analyzed, for the first time, the expression of TLR4 in PBMC from kidney recipients with contrasted situations: operational tolerance and chronic immune-mediated rejection (Banff 2005), compared to patients with normal histology and stable graft function, non transplant patients with renal failure and healthy volunteers.
cord-009813-o8ai730r	2019	
cord-011436-ud35mf5l	2020	It was also found that rRABVs expressing IFN-λ could reduce the production of inflammatory cytokines in primary astrocytes and microgila cells, restrict the opening of the blood-brain barrier (BBB), and prevent excessive infiltration of inflammatory cells into the brain, which could be responsible for the neuronal damage caused by RABV. To further characterize the role of IFN-λ in RABV infection in the mouse model, recombinant RABVs (rRABVs) expressing murine IFN-λ2 or IFN-λ3, designated as rB2c-IFNλ2 and rB2c-IFNλ3 respectively, were constructed as shown in Figure 2A , and rescued as described previously [27] . To further investigate whether IFN-λ restricts RABV infection in vivo, groups of five-week-old female BALB/c mice were mock-infected with DMEM or inoculated with B2c, rB2c-IFNλ2, or rB2c-IFNλ3 by different routes. Expression of neuronal CXCL10 induced by rabies virus infection initiates infiltration of inflammatory cells, production of chemokines and cytokines, and enhancement of blood-brain barrier permeability
cord-011438-imbpgsub	2020	
cord-012418-6ralcn8p	2020	
cord-012497-n5pu1yeu	2020	Finally, we sought to understand the in vivo role of STAT2 by infecting hSTAT2 knock-in mice with HMPV, and found that mice had increased weight loss, inhibition of type I interferon signaling, and a Th2-polarized cytokine profile compared to WT mice. Mouse models for HMPV have been developed, but mice are only semi-permissive for HMPV, requiring a high viral inoculum for productive in vivo infection ( [25] and unpublished observations), which may be due to species differences in the innate immune proteins antagonized by the virus. To better understand the global consequences of substituting human STAT2 into mice in vivo, we performed multiplex cytokine analysis on lung homogenates of HMPV-infected hSTAT2 KI and WT mice at day five after high-dose inoculation, as day five represents a time point that bridges innate and adaptive immunity.
cord-012909-o6t2srim	2020	
cord-013280-kczj24se	2020	
cord-013481-3zwq67do	2020	The Type I Interferons (IFN-Is) are innate antiviral cytokines that include 12 different IFNα subtypes and IFNβ that signal through the IFN-I receptor (IFNAR), inducing hundreds of IFN-stimulated genes (ISGs) that comprise the ''interferome''. Since IFNβ, and not IFNα, is upregulated during chronic HIV-1 infection in the gut, we compared core ISGs and IFNβ-specific ISGs from colon pinch biopsies of HIV-1-uninfected (n = 13) versus ageand gender-matched, antiretroviral-therapy naïve persons with HIV-1 (PWH; n = 19). We recently reported that during chronic, untreated HIV-1 infection, IFN-I inducible antiretroviral genes APOBEC3G, BST2 and MX2, as well as IFNβ, but not IFNα, were expressed to significantly higher levels when compared to HIV-1 uninfected individuals [38] . These data suggest that increased IFNβ in the gut of chronic PWH may drive genes associated with sustained ISG expression, antigen processing, T cell activation, inflammation and immune exhaustion.
cord-015021-pol2qm74	1994	It is our current understanding that LPS is responsible for many of the pathophysiological events observed during gramnegative infections and that one of the major mechanisms leading to shock and death is the LPS-induced activation of macrophages resulting in the production and release of lipid and peptide mediators, among which tumor necrosis factor seems to be the most important. However plasma IL-6 estimation revealed a statistically significant reduction at 6 hours in tanrine-treated animals compared to glycino and TW controls ( Objective: To evaluate the effects of allogeneic blood transfusion, thermal injury and bacterial garage on interteukin 4 (IL-4), tumor necrosis factor alpha (TNF) production and host mortality and to study if the administration of thymopentth (THY) could affect these events.
cord-015147-h0o0yqv8	2014	Cyclooxygenases (COX) catalyze the first step in the synthesis of prostaglandins (PG) from arachidonic acid.COX-1 is constitutively expressed.The COX-2 gene is an immediate early-response gene that is induced by variety of mitogenic and inflammatory stimuli.Levels of COX-2 are increased in both inflamed and malignant tissues.In inflamed tissues, there is both pharmacological and genetic evidence that targeting COX-2 can either improve (e.g., osteoarthritis) or exacerbate symptoms (e.g., inflammatory bowel disease).Multiple lines of evidence suggest that COX-2 plays a significant role in carcinogenesis.The most specific data that support a cause-and effect relationship between COX-2 and tumorigenesis come from genetic studies.Overexpression of COX-2 has been observed to drive tumor formation whereas COX-2 deficiency protects against several tumor types.Selective COX-2 inhibitors protect against the formation and growth of experimental tumors.Moreover, selective COX-2 inhibitors are active in preventing colorectal adenomas in humans.Increased amounts of COX-2-derived PGE2 are found in both inflamed and neoplastic tissues.The fact that PGE2 can stimulate cell proliferation, inhibit apoptosis and induce angiogenesis fits with evidence that induction of COX-2 contributes to both wound healing and tumor growth.Taken together, it seems likely that COX-2 induction contributes to wound healing in response to injury but reduces the threshold for carcinogenesis.
cord-016343-wc3i54fc	2008	RdRp, RNA-dependent RNA polymerase; IRES, internal ribosome entry site; 5BSL3.2, stem loop 3.2 within the coding sequence of NS5B normally result in the production of type I IFNs and the subsequent expression of IFN-induced effector proteins, which in turn would establish an antiviral state in the IFN-producing cell itself and in neighboring cells. Since MxA has the ability to efficiently inhibit a variety of different RNA viruses, MxA was the first IFN-induced effector protein to be analyzed for its antiviral activity in the HCV replicon system (Frese et al., 2001) . Rather indirect evidence that the OAS/RNase L pathway may indeed target HCV replication/translation was recently provided by Taguchi and co-workers, who reported that the N-terminal portion of NS5A (amino acids 1 to 148), which lacks the so-called PKR-binding domain, binds to OAS proteins and there by counteract the antiviral activity of IFN-α (Taguchi et al., 2004) .
cord-016499-5iqpl23p	2014	
cord-017184-1ewi3dka	2008	In this disease, microorganism phagocytosis by polymorphonuclear (PMN) leukocytes appears annulled, and the patient is subject to severe infections supported by capsular bacteria: the deficiency, described in association with severe and recurrent infantile infections [175, 485, 487] , depends on the lack of mannose-binding lectin (MBL) [487] , its Primary Immunodeficiencies a possible atopy dependence on IgA underproduction rather than on IgE hyperproduction ( Fig. 4.1 ): in children with levels of IgA at the minimum normal level, and followed from birth until the age of 18-23 months, a greater severity of atopic manifestations and an increased cumulative incidence of asthma, AD and otitis media with effusion (OME) were observed compared to controls.
cord-017785-zwnkrs23	2018	The role of bats as natural reservoirs of a variety of high-profile viruses that are highly pathogenic in other susceptible species yet cause no clinical disease in bats has led to a resurgence of interest in their immune systems. RNAseq studies on tissues and cells from a variety of different species of bats have provided evidence that bats have nearly all of the major components of the immune system that are present in other mammals, including receptors and molecules associated with innate and adaptive immunity and microRNAs (Papenfuss et al. Responses to antigens such as ϕX174 bacteriophage and sheep red blood cells have demonstrated that the generation of neutralizing antibodies is delayed in the big brown bat, the pteropid bat, and the Indian flying fox (Pteropus giganteus) (Hatten et al.
cord-020717-niiib47f	2003	
cord-021872-rhi7hi9m	2015	Topical antiviral therapy has been mainly used for herpetic ocular disease, but studies have evaluated a systemic antiviral compound (famciclovir) for treatment of multiple clinical syndromes associated with FHV-1 infections. 7 A related drug, (R)-9-(2-phosphonylmethoxypropyl)-2,6diaminopurine (PMPDAP), has been shown previously to be a potent inhibitor of FIV replication in cell culture and has reduced the viral load in three of four cats experimentally infected with FIV when treated at 20 mg/kg SC three times per week for 6 weeks. 1 A prodrug of acyclovir, valacyclovir, was developed for increased bioavailability in humans, but use for FHV-1 treatment in experimentally infected cats induced fatal renal and hepatic necrosis and bone marrow suppression, and did not reduce viral shedding or clinical disease severity. 20 Even though this study did not mimic how cats with natural infection would be treated, results from a clinical case study suggested this drug is likely effective for treatment of clinical cases, though it was not blinded and placebo controlled.
cord-022226-qxp0gfp3	2007	
cord-022631-s4n24xij	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-022888-dnsdg04n	2009	Methods: Phospho-specific Western blot analyses were performed to verify the functionality of the different IFN-g pathway components, intra-and extracellular flow cytometry experiments were employed to determine the expression of antigen processing components and HLA class I cell surface antigens, quantitative real time-PCR experiments to confirm the absence of JAK2 and presence of pathway relevant molecules as well as, genomic PCR and chromosome typing technique to prove the deletion of JAK2. In order to accomplish these objectives we induced priming or tolerance of ovalbumin (OVA 323-339 peptide)-specific T cells from DO11.10 TCR transgenic mice in vitro or, following adoptive transfer of near physiologically relevant numbers of such cells into recipients, in vivo and correlated functional outcome (via proliferation and cytokine readout assays or antibody production) with E3 ubiquitin-protein ligases expression and the ubiquitination status of the TCR signalling machinery.
cord-023017-k6edtg58	2006	
cord-023033-tgt69ir6	2006	Methods: We performed a retrospective analysis comparing outcomes, and the incidence, timing, and severity of histologic recurrence of HCV following transplantation in patients who underwent living donor liver transplant compared to recipients of cadaveric organs. Local liver immune responses are thought to play a major role in chronic autoimmune diseases directed at biliary epithelium.Using the apical sodium dependent bile acid transporter (ASBT) promoter to drive biliary epithelial cell -specific expression of a membrane form of ovalbumin (OVA), we have previously developed OVA-BIL transgenic mice. Thus, our AIM was to ascertain whether Kupffer cells express death ligands and contribute to hepatocyte apoptosis and liver fibrosis in the bile duct ligated mouse, an animal model of cholestasis. Control experiments confirmed that Y2 protein inhibited IFNa-induced ISRE-mediated signaling in Huh-T7 cells; relative luciferase activity was reduced from 653 (pH771 IFNP nAb increased HCV core Ag replication by 42% and 23% compared to no treatment (p=O.O1).
cord-023143-fcno330z	2004	Based on a variety of experimental evidence, it is clear that demyelination induced in SJUJ mice by infection with the BeAn strain of TMEV is a Thl-mediated event: (a) disease induction is suppressed in T cell-deprived mice and by in vivo treatment with anti-I-A and anti-CD4 antibodies; (b) disease susceptibility correlates temporally with the development of TMEV-specific, MHC-class Il-restricted DTH responses and with a predominance of anti-viral lgG2a antibody; (c) activated (Le., lL-2RC) T cells infiltrating the CNS are exclusively of the CD4+ phenotype, and (d) proinflammatory cytokines (IFNq and TNF-p) are predominantly produced in the CNS. These results have important implications for a possible viral trigger in MS as they indicate that chronic demyelination in TMEV-infected mice is initiated in the absence of demonstrable neuroantigen-specific autoimmune responses and are consistent with a model wherein early myelin damage is mediated via primarily by mononuclear phagocytes recruited to the CNS and activated by pro-inflammatory cytokines produced by TMEV-specific Thl cells.
cord-023306-3gdfo6vd	2010	Conflict of Interest No. Purpose We examined age trends in the distribution of stage at diagnosis in patients presenting with non-small cell lung cancer (NSCLC) at tertiary hospitals. Methods Eleven healthy male subjects, aged 28(8) (SD) years completed separate visits with (a) no restriction and (b) chest wall strapping to reduce FVC by 30 (7) Introduction Glossopharyngeal breathing (GPB) is used by competitive breath-hold divers to increase lung gas content above TLC to improve performance. Our DC culture results showed that both MHC-I and MHC-II expression on DCs from COPD were significantly down regulated compare to healthy controls, which could affect MHC restricted Ag presentation, and lead to a failure to activate responder T cells.
cord-023372-ft8cp9op	2008	
cord-023373-6wh1kb3p	2008	
cord-023374-87ob1exq	2008	
cord-023375-x4p187u7	2008	
cord-023387-tyeh14wz	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023388-btbf6wkg	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023389-ilrp8vb7	2008	
cord-023390-5hcgdlmt	2008	
cord-023391-bq5w3jk9	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023392-axd0901z	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023393-8nye3nc8	2008	
cord-023394-ptfjxpo6	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023402-8qfmo6rq	2008	
cord-023403-jzdrvfvr	2008	
cord-023407-s85g7g0x	2008	
cord-023410-eblcf902	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023411-iszb5qlk	2008	
cord-023414-xxw5kptr	2008	
cord-023415-hhvmsn5b	2008	
cord-023417-by18aczt	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023419-lnmc6vv5	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023421-1d1gf7az	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023425-3sjsogvq	2008	
cord-023429-x52gbklw	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023430-5zuewjv2	2008	
cord-023431-zjyrhlxn	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023433-d1b7qvhs	2008	
cord-023438-g0k0vvdc	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023439-r04y1j22	2008	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients.
cord-023441-q83y12sk	2008	
cord-023443-pvz7dll9	2004	We demonstrate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN-g responses to peptides from K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. The uptake of MBP by B cells and the presentation of MBP-derive peptides to T helper (Th) cells by B cells may be promoted by the formation of complement (C) activating immune complexes (ICs) between MBP and natural autoantibodies in healthy individuals and disease-associated anti-MBP antibodies in MS patients, respectively. While MBP did not induce measurable proliferation of B cells nor CD4 þ T cells, we observed the production of TNF-a, IFN-g and IL-10 by PBMC in response to incubation with MBP in the presence of sera from healthy controls as well as sera from MS patients. In conclusion, the results of this study suggest an involvement of the ASMase in the activation, expansion or maturation of virus-specific CD8 þ T cells during the acute infection of mice with the LCM virus.
cord-023445-c4tqioz1	2008	
cord-023585-n3lr9z3u	2003	Robert Phillpotts describes the mechanism of interferon action and the future hopes and developments for its use in preventing colds. l~''obert Phillpotts describe~ the mechanism of interferon action and the future hopes and developments for its use in preventing colds. Interferon appears to be the ideal antiviral drug for use in preventing colds; it is extremely potent, and active against a wide range of viruses. intranasal interferon prevents colds In an initial experiment at the Common Cold Unit in Wiltshire, UK, intranasal administration of partially purified human leucocyte interferon to volunteers was shown to prevent colds caused by rhinovirus type 4 (Ref. 5). This question was answered in a further experiment carried out in 1982, in which HulFN a, purified to virtual homogeneity on a monoclonal antibody affinity column was shown to prevent colds caused by another rhinovirus, type 9 (Ref. 6).
cord-023724-5at0rhqk	2015	
cord-024651-578c9ut5	2020	Abstract/Case Report Text Introduction: Mutations in the gene encoding signal transducer and activator of transcription 3 (STAT3) cause autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES) characterized by recurrent skin and sinopulmonary infections, atopic dermatitis, and elevated serum immunoglobulin E (IgE) levels. Objective: The purpose of this study is to increase awareness and improve diagnosis of primary immune deficiency (PID) in the heterogenous group of patients with autoimmune cytopenia (AIC) by identifying clinical characteristics and laboratory biomarkers that distinguish those with underlying PID, disease activity and guide mechanism-based targeted therapy. 7 Chief, Laboratory of Clinical Immunology and Microbiology/National Institute of Allergy and Infectious Diseases, NIAID/National Institutes of Health, NIH Abstract/Case Report Text We have previously used the artificial thymic organoid (ATO) system, based on the 3D aggregation and culture of a delta-like canonical Notch ligand 4-expressing stromal cell line (MS5-Dll4) with CD34+ cells, to study T cell differentiation from CD34+ cells obtained from patients carrying defects that are intrinsic to hematopoietic cells (RAG1-2, AK2, IL2RG) or that affect thymus development (DiGeorge syndrome).
cord-025181-eg108wcd	2020	In this study, with biologically cloned viruses from a single clinical isolate, we have established two mouse models of DENV infection, one is severe lethal infection in immunocompromised mice, and the other resembles self-limited disease manifestations in Balb/c mice with transient blockage of type I IFN responses. Further, we compared the infectivity of these two viral variants in a self-limited infection model, in which type I IFN receptor of wild-type Balb/c mice had been transiently blocked before infection, and found only the virus strain exhibiting larger plaque size caused infectious viral particles in sera. We have recently developed a ZIKV infection model in Balb/c mice with transient blockage of type I IFN Fig. 2 Phylogenetic analysis of DENV-2 1D4-5-SP and DENV-2 8H2-7-LP with representative serotype-2 dengue viruses of different genotypes isolated from different geographical regions.
cord-028945-p3hhd5ed	2020	Thereafter, we developed a hexavalent recombinant protein vaccine adjuvanted with Montanide ISA 50 V and administered to a murine model to determine its immunogenicity and protection efficiency against lethal toxoplasmosis. Hexavalent recombinant protein mixture (+) Montanide ISA 50 V vaccine induced significantly high levels of IgG1 and IgG2a at day 42 compared to the controls groups (P < 0.001, **). Overall, in mice administered with Hexavalent recombinant protein mixture (+) Montanide ISA 50 V, IgG2a and IgG1 levels showed a strong and balanced immune response. Overall, the Th1 part of the immune response elicited by hexavalent recombinant protein mixture (+) Montanide ISA 50 V induced significant levels of CD4 + and CD8 + T lymphocytes secreting IFN-γ and conferred significant protection in Swiss Outbred mice challenged with lethal dose of T.
cord-029488-l11ufs6k	2020	Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways. We thus examined whether expression of VEGF in human pulmonary microvascular endothelial cells is regulated by MAPKs. When HPMEC-ST1.6R cells were treated with PD98059, an inhibitor of MAPK kinase which is an ERK1/2 upstream activator, or SB203580, which is widely used as a specific inhibitor of p38 MAPK, the LPS/IFN-γinduced increase in VEGF protein levels was strongly blocked (Fig. 4b) .
cord-032183-yqqqe325	2019	Patients awaiting liver transplantation because of HBV-related end-stage liver disease or liver cancer should be given nucleoside analogues with strong HBV inhibition and low drug-resistance, or nucleotides analogues combination treatment, in order to reduce viral load and prevent graft re-infection. The objective of antiviral treatment for HBV-ACLF is to reduce viral load at an appreciably high rate, thereby promoting reduction in hepatocyte cell death and improved survival outcomes by prevention of decompensation related multiorgan complications in this group of severely ill patients. Response-Guided Therapy 4006 study [126] suggested continuous treatment with LAM (10 years) delayed clinical progression in patients with chronic hepatitis and advanced fibrosis by significantly reducing the incidence of the risk of hepatocellular carcinoma and hepatic decompensation.
cord-034467-jh9msz1c	2020	In the present study, we examined the expression of important koala cytokines, immune markers and host restrictions factors to determine their pre-and post-vaccination levels in northern koalas harbouring endogenous KoRV. Genes targeted included nine cytokines (CCL4L, Interleukin Open Access *Correspondence: oolagoke@usc.edu.au Genecology Research Centre, University of the Sunshine Coast, Sunshine Coast, QLD, Australia (IL)-1β, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-18 and Interferon gamma (IFN-γ), four host restriction factors (BST2, ISG15, RSAD2 and TRIM1) and two T-cell markers (CD4 and CD8β). In addition, none of the host restriction factors tested (BST2, ISG15, RSAD2 and TRIM1) had significant changes in their expression either at 4-or 8-weeks post-vaccination when compared to prevaccination levels. In this cohort of KoRV vaccinated and endogenously infected koalas, a small but significant increase in the expression of IFN-γ at both 4-and 8-weeks post-vaccination was observed, compared to pre-vaccination levels. Our study investigated the expression of four host restriction factors in koalas harbouring endogenous KoRV: BST2, ISG15, RSAD2 and TRIM1.
cord-048485-b8xb1f12	2008	
cord-048489-ajafw966	2008	title: Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity RESULTS: IL-1β, IFN-γ, IL-4, IL-6, IL-13, IL-7 and GM-CSF were significantly increased in patients with severe clinical manifestations (severe dengue) when compared to mild disease forms (mild dengue). Analysis of factors independently associated with dengue severity and other clinical manifestations was performed with GLM with logistic regression or Gaussian family. In order to avoid effects due to differences in the blood collection time, we compared mild and severe dengue patient groups using Mann-Whitney U Test, which showed no differences in the disease onset time at the moment of sample collection [see Additional file 1]. We studied the cytokine profile from Brazilian patients in order to compare severe and mild dengue cases during the acute phase of the disease. In the present study, the use of a multiplex analysis for cytokine plasma detection in patients with dengue could identify cytokine profiles associated with the disease severity.
cord-103511-31njndob	2020	
cord-103625-p55ew8w7	2020	
cord-103675-21qu87oh	2004	
cord-252268-o63ep08b	2014	
cord-252485-cxi3cr15	2015	
cord-252528-rgnhfcbx	2020	• Anti-inflammatory therapies, including tocilizumab, chloroquine, and hydroxychloroquine, which can be promising treatment to control excessive cytokine release in severe COVID-19, have the potential to reduce the risk of vascular thrombotic events, but more clinical data are needed for optimum instruction of drug use and drug selection. By interpreting the pathological mechanisms, we aim to illustrate that excessive pro-inflammatory cytokine release and potential ACE2 down-regulation can promote the hypercoagulable state in severe COVID19 , and propose that the anti-inflammatory medications, as well as ACEI/ARB, can benefit severe COVID-19 patients by reducing the risk of vascular thrombotic events.
cord-252568-b8sbvy0g	2017	There is evidence that these particles display adjuvant characteristics, promoting cell recruitment, antigen-presenting cell activation, cytokine production, and inducing a humoral immune response. However, many NPs have been shown to stimulate immune responses, including cell recruitment, activation of antigen (Ag)-presenting cells (APCs), and induction of cytokine and chemokine release. Among the vaccines targeting extracellular bacteria and toxin, two were formulated with lipopolysaccharide (LPS) in glycopeptide Ag. The use of glycoantigen and LPS can trigger an intense response through TLR4 and B cell receptor activation; the presence of gold NPs (AuNPs) may have minimal influence on this response. To understand the possible uses of MeNPs as platforms for vaccines against infectious diseases, analysis is needed of the impact of different physicochemical characteristics of NPs on the innate immune response (Figure 1) .
cord-252671-uf96jgig	2016	
cord-252772-f3fctcru	2020	
cord-252950-eiphxwmn	2020	COVID patients in ICU present a high mortality rate and immunoprofiling reveals heterogeneous IFN-α2 production with about 20% of critically-ill patients unable to produce IFN-α2, highlighting the immune response heterogeneity and opening avenues for targeted therapies. 42 Capsule summary: 43 COVID patients in ICU present a high mortality rate and immunoprofiling reveals heterogeneous α2 production with about 20% of critically-ill patients unable to produce IFN-α2, highlighting the 45 immune response heterogeneity and opening avenues for targeted therapies. Various immunosuppressive drugs, including IL-6 blockers or JAK-STAT signaling inhibitors have been 56 suggested for the treatment of SARS-COV-2 infection 2 whereas additional clinical trials are evaluating 57 the use of recombinant interferon to foster host antiviral response. To date, IFN-I response has not been evaluated in COVID-19 60 patients and its contribution to the viral control and inflammation is unknown. We further explored a larger cohort of 26 critically ill COVID patients from one of the intensive care 75 unit (ICU) at Hospices Civils de Lyon (Lyon, France).
cord-253077-61fmul8c	2020	
cord-253335-wgqierp6	2020	
cord-253501-hkxlq3os	2018	
cord-253743-hj9mq6lq	2007	
cord-253862-jl1zhg13	2020	Although this novel virus is less severe than the first SARS-CoV outbreak, human-to-human transmission remains very high and the number of cases continues to rise exponentially in major urban areas, highlighting the urgent need to develop new containment, diagnostic, and treatment protocols. In the case of SARS-CoV-2, viral evasion of the innate immune system leads to an increase in cytokine production and late CD4+/CD8+ response, which then leads to pathogenic inflammation in patients with high viral loads. (ChiCTR2000029308), involving severe SARS-CoV-2 cases, compared lopinavir/ritonavir treatment with standard care alone, and they showed that the antivirals yielded no clinical benefits. In an open-label control study conducted by Cai et al., the antiviral activity of favipiravir + IFN-α was compared to that of lopinavir/ritonavir + IFN-α in patients with confirmed SARS-CoV-2 infection.
cord-254192-86ksgl5t	2019	
cord-254492-42d77vxf	2016	Here we review how hostand virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression. Methods for this include substrate molecular mimicry, binding and blocking E3-substrate pairs, expressing virally encoded E3s/DUbs, and hijacking host E3s/DUbs. Additionally, a novel mechanism involving ubiquitin chain packaging into nascent virions for subsequent redeployment Viral infection activates danger signals that are transmitted via the retinoic acid-inducible gene 1-like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. Here we review how host-and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression. RNF125 forms part of this process, ligating K48-linked polyubiquitin chains to the activated CARD of RIG-I and MDA5, leading to proteasome-mediated degradation of both receptors and diminished IFN-I signaling. MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors
cord-254747-vox5xsgd	2018	
cord-254895-ym0jsir5	2008	
cord-255013-njpuc475	2014	
cord-255034-x100xo2t	2020	
cord-255607-dbexsugq	2020	
cord-255709-tm3we5sd	2006	It has been previously shown that treatment of cells with both type I and type II IFN produces an antiviral state greater in magnitude than can be explained by additive effects alone. Cytopathic effect (CPE) was extensive in vehicle-treated groups infected with either SARS-CoV strain at 120 hpi ( Fig. 2A and 2E) , as evident by the reduced monolayer staining with crystal violet. However, the CPE profile observed in Calu-3 cells suggests that the synergistic inhibitory effect on SARS-CoV replication by IFN-β and IFN-γ is not Vero E6 cell specific. It has been known for more than 25 years that treatment of cells with type I and type II IFN potentiates the antiviral response to levels greater than can be explained by simple additive effects. Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) Synergistic inhibition of human cytomegalovirus replication by interferon-alpha/beta and interferon-gamma
cord-255773-b4re5bky	2016	title: Suppression of type I interferon production by porcine epidemic diarrhea virus and degradation of CREB-binding protein by nsp1 We showed that PEDV suppressed the type I interferon production and ISGs expression in these cells, and identified nsp1, nsp3, nsp7, nsp14, nsp15, nsp16, E, M, N and ORF3 as the viral IFN antagonists. The CBP degradation is a novel mechanism of coronavirus nsp1 for IFN suppression and our study provides a new insight into the immune modulation and evasion strategy of PEDV. MARC-145 cells have been used to study type I IFN signaling of porcine arterivirus (Kim et al., 2010; Overend et al., 2007; Patel et al., 2010) , and thus infection of these cells One μg of each of the cloned genes was transfected to HeLa cells in 12-well plates, and protein expression was determined by immunofluorescence (B) and
cord-255781-55zrmgxq	2011	
cord-255997-oer5lxxr	2020	Here, we have studied the interaction of isolated primary SARS-CoV-2 viral strains with human plasmacytoid pre-dendritic cells (pDC), a key player in antiviral immunity. Importantly, all major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine, including P2and P3-pDC differentiation, the expression of maturation markers, and the production of interferon-α and inflammatory cytokines. Interestingly, pDC responded to SARS-CoV-2 by a complete activation program, including diversification into effector subsets, production of type I and type III IFN, as well as inflammatory cytokines. We also showed that hydroxychloroquine, an antimalarial drug proposed for treatment of COVID-19 patients (Das et al., 2020; Mahévas et al., 2020) , inhibits SARS-CoV-2-induced pDC activation and IFN production in a dose-dependent manner. Following 24 hours of culture, we found that HCQ inhibited pDC diversification in response to SARS-CoV-2, which is similar to the decrease observed with Flu, used as a positive control ( Fig 4A) .
cord-256187-ofp7tupv	2012	
cord-256293-5lpe8hg2	2020	title: Jinhua Qinggan granule, a Chinese herbal medicine against COVID-19, induces rapid changes in the plasma levels of IL-6 and IFN-γ However, in China, traditional Chinese herbal medicines have provided therapeutic benefit to patients with COVID-19. Jinhua Qinggan granule (JHQGG) is a Chinese multi-herbal formula previously developed for the treatment of H1N1 influenza and has been encouraged for patients clinically suspected of COVID-19 during medical observation. On the basis of its therapeutic efficacy for influenza, JHQGG has been recommended for patients clinically suspected of COVID-19 during medical observation. Notably, in blood cytokine analysis, the plasma levels of IL-6 and IFN-γ were significantly decreased and increased, respectively, compared with those in pre-administration (IL-6, 2.75 vs. The rapid immunomodulatory effects of JHQGG may be able to remedy the immune dysregulation observed in COVID-19 patients All rights reserved. Herbal medicine for the treatment of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis of randomized controlled trials
cord-256325-q70rky3r	2017	title: A Functional Genomics Approach to Henipavirus Research: The Role of Nuclear Proteins, MicroRNAs and Immune Regulators in Infection and Disease Here we largely focus on findings from two recent RNAi screens to identify protein-coding genes and host-encoded microRNAs impacting the henipavirus infection cycle in human cells. X-ray data have suggested that the methylation of rRNA requires the formation of this complex with involvement of four fibrillarin molecules interacting with different regions of the target rRNAs. The yeast equivalent of fibrillarin, NOP1, has been more extensively studied than the human counterpart but fibrillarin is a well-conserved protein in most organisms, reinforcing the notion that all post-transcriptional processes involving fibrillarin such as chemical modification (methylation) of rRNA, pre-rRNA cleavage and ribosome assembly are essential for proper cellular functioning (Rodriguez-Corona et al. Deffrasnes and colleagues showed that siRNA-mediated knockdown of fibrillarin expression dramatically reduced HeV protein production and viral genome replication but did not impact viral fusion, and that fibrillarin catalytic activity was essential to henipavirus infection.
cord-256788-h4iv8crq	2012	
cord-256816-gd7y3ggj	2020	
cord-256838-8rzibpbl	2019	
cord-256998-or73in8m	2020	Among the more notable responses in other early preclinical studies, nearly half of mice bearing established B16F10 melanomas experienced complete tumor regression following 2 weekly treatments with pIL-12+EP (124) . In preclinical studies, a single intratumoral injection of mRNA encoding murine IL-12 (mIL-12) increased IFNγ expression and genes associated with a Th1 response in MC38 tumor-bearing mice (190) . In a useful comparison against other cytokines, one study demonstrated that Ad-IFN-γ had no greater antitumor activity than an empty Ad vector, whereas AdmIL-12 induced complete regressions of P815 mastocytomas in >80% of treated mice (219) . Antitumor activity on xenografts of human lung tissues indicated that liposomal encapsulation is a promising approach capable of eliminating tumor cells and inducing lymphocyte infiltration 2 weeks after i.t. injection. Immunotherapy of established tumors in mice by intratumoral injection of an adenovirus vector harboring the human IL-2 cDNA: induction of CD8 + T-cell immunity and NK activity
cord-257077-cdnkk6ou	2013	
cord-257116-6td3efjw	2017	
cord-257220-fe2sacjj	2014	LDV elevates IgG levels in mice with little production of virus-specific antibodies [11, 21] , which is almost identical to what is seen in isolator piglets infected with PRRSV [22] (''''The effect of age, rearing, complement and the role of mucosal immunity'''' section). Polyclonal activation of B cells occurs in lymphoid organs from porcine reproductive and respiratory syndrome virus (PRRSV)-induced pigs The presence of alpha interferon at the time of infection alters the innate and adaptive immune responses to porcine reproductive and respiratory syndrome virus Interferon type I response in porcine reproductive and respiratory syndrome virus-infected MARC-145 cells Antigen-specific B cell responses to porcine reproductive and respiratory syndrome virus infection Antibody production and blastogenesis response in pigs experimentally infected with porcine reproductive and respiratory syndrome virus Neutralizing antibody responses of pigs infected with natural GP5 N-glycan mutants of porcine reproductive and respiratory syndrome virus
cord-257662-viy65y72	2014	
cord-258286-lodjcj8c	1997	Previous studies have shown that immunocoma large plaque variant derived from the parental JHM petent mice infected with MHV exhibited increased exstrain (Stohlman et al., 1982) ; the small plaque variant pression of a number of cytokines, including IL-1, IL-6, DS (Stohlman et al., 1982) ; the neutralization-escape mu-TNF-a, and IFN-g, in the CNS at the time of viral cleartant 2.2-V-1 (Fleming et al., 1987; Wang et al., 1992) , and ance (Pearce et al., 1994) . The expressed IFNg exhibited antiviral activity, prevented virus spread in layers of DBT cells grown at approximately 70% confluence in 60-mm petri dishes were infected with MHV at vitro, and altered viral pathogenesis in mice. Expression of IFN-g using an MHV DI RNA vector cell metabolism prior to infection or it may be that interferon acts at an early stage of viral replication.
cord-258685-ayek8zbo	2020	
cord-258691-cd83w9o6	2009	IFN-γ-mediated control of JHMV replication is dampened in glial cultures derived from the neural progenitor cells of type I receptor knock-out mice. These data indicate that JHMV is capable of infecting glial cells generated from neural progenitor cells and that IFN-γ-mediated control of viral replication is dependent, in part, on type I IFN secretion. In the present study, we demonstrate that primary cultures of glia derived from neural progenitor cells are susceptible to JHMV infection and support viral replication. Therefore, these findings provide, to our knowledge, the first demonstration that glia-committed cells derived from neural precursors are susceptible to JHMV infection as well as identify a potential mechanism responsible for controlling viral replication. These findings indicate that differentiated cells derived from neural progenitors are susceptible to JHMV infection and are capable of supporting replicating virus which results in extensive cytopathology.
cord-259669-fod4xkd7	2008	Being strategically located at sites of pathogen entry, such as mucosal surfaces and Considering the pivotal roles played by dendritic cells (DCs) in both innate and adaptive immune responses, advances in the field of porcine immunology DC biology have recently progressed rapidly. The function of porcine monocyte-derived DC has not only been characterized in terms of antigen presentation and lymphocyte activation, but also their response to various ligands of pattern recognition receptors. The function of porcine monocyte-derived DC has not only been characterized in terms of antigen presentation and lymphocyte activation, but also their response to various ligands of pattern recognition receptors. Altogether, the co-expression of CD172a and CD1 along with relatively high levels of both CD80/86 and MHC class II represent phenotypic characteristics of porcine MoDC but no marker clearly differentiating them from monocyte-derived macrophages has been identified.
cord-259748-x7dq1sy4	2020	Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immune-surveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. In 2008, several research teams discovered a new protein on the endoplasmic reticulum (ER) which can be activated by immune-stimulatory DNA (ISD) and initiate type-I interferon (IFN) responses, which was named "stimulator of interferon genes" (STING, also known as MITA, ERIS) (2) (3) (4) . Mitochondrial outer membrane permeabilization (MOMP) activation, which is executed by BCL-2-associated X protein (BAX) and BCL-2 antagonist or killer (BAK), is a highly controlled conserved process in regulated cell FIGURE 3 | Interaction of the cGAS-STING pathway with other DNA-sensing pathways and its role in cell survival. Human plasmacytoid dentritic cells elicit a Type I interferon response by sensing DNA via the cGAS-STING signaling pathway
cord-260109-vgbrwegt	1990	
cord-260291-zfpcuhpy	2011	
cord-260729-b12v3c8c	2007	
cord-261028-sxux2ujo	2017	Dendritic cells (DCs) are a heterogeneous population of professional antigen-presenting cells (APCs) from hematopoietic origin that serve as a key link between the innate and adaptive immune systems, and are the lynchpin in generating anti-tumor immunity (Steinman and Idoyaga, 2010) . More recently, type I IFN production and signaling through the STING pathway has been identified as having an essential role in the development of anti-tumor immunity in response to tumor derived DNA. DNA sensing by STING is the upstream link that triggers type I IFN production by DCs and facilitates effective cross-priming of tumor specific CD8+ T cells. This DNA is likely derived from stressed and dying cancer cells, and is introduced into the DC cytosol through a yet unknown mechanism where it binds to cGAS, which initiates STING mediated type I IFN transcription (Fig. 2) .
cord-261380-xms5su6w	2020	Among an open-label, randomized clinical trial, adult patients (≥ 18 years old) with severe COVID-19 were randomly assigned (1:1) to the IFN group or the control group. According to the presence of this evidence, IFN β was considered as a promising option for the treatment of In this open-label, randomized clinical trial, efficacy and safety of IFN β-1b in the treatment of patients with severe CoVID-19 were assessed. This open-label, randomized clinical trial was designed to evaluate the efficacy and safety of IFN β-1b in the treatment of patients with CoVID19 Adult patients (≥ 18 years old) with positive PCR and clinical symptoms/signs of pneumonia (including dyspnea, cough and fever), peripheral oxygen saturation (SPO 2 ) ≤ 93 % in ambient air or arterial oxygen partial pressure to fractional inspired oxygen (PaO 2 /FiO 2 ) < 300 or SPO 2 /FiO 2 < 315 and lung involvement in chest imaging were included.
cord-262673-j2ot35lt	2020	Furthermore, respiratory epithelial cells and lung macrophages are capable of secreting a broad range of chemokines like IL-8, Macrophage inflammatory protein-1 (MIP-1), RANTES and cytokines including TNF-α, IL-6, IL-1β that influence the types of immune cells being recruited to the area in response to acute viral infections (177, 178) . Both Influenza and SARS virus can induce acute lung injury (ALI) which is accompanied by high levels of C5a, leading to the influx and activation of innate immune cells (199) (Figure 1) . Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocytederived macrophages and dendritic cells Dynamic innate immune responses of human bronchial epithelial cells to severe acute respiratory syndrome-associated coronavirus infection Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells
cord-263141-n200x6z1	2016	
cord-263200-ntq1f4ix	2016	To initiate an effective antiviral response, RNA viruses are recognized by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and then trigger multiple signaling pathways to promote the production of proinflammatory cytokines, including type I IFNs [1] [2] [3] [4] . In this study, we demonstrate for the first time that HACE1 contributes to negative regulation of the virus-induced type I IFN signaling via disrupting the MAVS-TRAF3 complex. HACE1 suppressed virus-induced type I IFN signaling independently of its ubiquitin E3 ligase activity. By a small-scale screening of unknown ubiquitin E3 ligases in the regulation of virus-induced type I IFN signaling by the dual-luciferase reporter, we identified HACE1 as a potential negative regulator in this pathway. By a small-scale screening of unknown ubiquitin E3 ligases in the regulation of virus-induced type I IFN signaling by the dual-luciferase reporter, we identified HACE1 as a potential negative regulator in this pathway.
cord-263433-oldy0gta	2015	
cord-263862-zzys31e9	2007	
cord-264121-4801f4o4	2013	
cord-265005-e6rpryrh	2014	We will discuss the expression patterns and functions of endosomal TLRs with regards to IFN production in uninfected specialized immune cell types, pDCs and XCR1 + DCs. Plasmacytoid DCs uniquely produce very large amounts of IFNs in response to in vitro stimulation with many viruses, without being infected (46) . Under these conditions, to promote health over disease, the benefits for the host of producing high circulating levels of IFNs in order to induce widespread cell-intrinsic anti-viral defenses might prevail over the deleterious effects that this could cause on certain cell types or tissues. Subcapsular sinus macrophages rapidly become infected by viruses incoming from the lymph and produce large amounts of IFNs. This altruistic suicide prevents virus dissemination to other adjacent cell types and promotes the induction of innate and adaptive anti-viral immunity (87) .
cord-265592-r8nlef0h	2001	
cord-265697-bbvlowyo	2020	
cord-265723-6k8196p2	2020	
cord-265941-eff4le0g	2020	Nevertheless, the signal transduction that follows pathogen recognition elicits numerous defence mechanisms, including the induction of inflammatory cytokine, chemokine and interferon production, activation of programmed cell death pathways, and inevitably an adaptive immune response, all of which contribute to pathogen control and elimination [1] . As inhibition of necroptosis does not affect IAV control, while Mlkl-/-Fadd-/-mice exhibit marked susceptibility to IAV-induced lethality [78] , it signifies that RIPK1/3-mediated apoptosis is a major form of host protection against IAV infection. A number of studies have used purified pathogen components such as LPS to investigate the outcomes of RIPK1/3-mediated inflammasome signaling, which appear to be largely dependent on cell type, stimulus, and the availability or functional activity of certain host signaling proteins [65, [123] [124] [125] [126] [127] . Overall this suggests that RIPK2 plays an important role in both innate and adaptive immunity to infection [137, 151] , and that RIPK2 was mediating these responses via NOD1/2 and not directly via TLR activation [140] .
cord-266679-gs1k7263	2009	
cord-266914-3eatplc2	2010	
cord-267099-rv6npz8z	2017	
cord-268341-103xf3dw	1997	
cord-268419-j90daoiq	2013	chagasi challenge infection, PBMCs from LBSap vaccinated dogs produced more IL-12, IFN-γ and concomitant nitric oxide (NO) when stimulated with Leishmania antigens as compared to PBMCs from respective control groups (saponin, LBtreated, or non-treated control dogs). chagasi challenge infection, PBMCs from LBSap vaccinated dogs produced more IL-12, IFN-␥ and concomitant nitric oxide (NO) when stimulated with Leishmania antigens as compared to PBMCs from respective control groups (saponin, LB-treated, or non-treated control dogs). Thus, the profile of different cytokines (IL-4, IL-10, TGF-␤, IL-12, IFN-␥, and tumor necrosis factor [TNF]-␣) and nitric oxide (NO) in supernatants of peripheral blood mononuclear cell (PBMC) cultures were evaluated before the first immunization (T 0 ), 15 days after completion of the vaccine protocol (T 3 ), and at time points 90 (T 90 ) and 885 (T 885 ) days after experimental L.
cord-268438-bjs5oliw	2019	
cord-269734-u43gt8fh	2016	
cord-270103-g9a72xf6	2018	
cord-270326-fzsczb8m	1991	
cord-270380-1me7ugkg	2020	Both proteins exhibited effective anti-vesicular stomatitis virus (VSV) activity in Vero, F81 (feline kidney cell), Madin–Darby bovine kidney (MDBK), Madin–Darby canine kidney (MDCK), and porcine kidney (PK-15) cells, showing broader cross-species antiviral activity than the INTERCAT IFN antiviral drug. Furthermore, the recombinant feIFN-ωa and feIFN-ωb proteins demonstrated antiviral activity against VSV, feline coronavirus (FCoV), canine parvovirus (CPV), bovine viral diarrhea virus (BVDV), and porcine epidemic diarrhea virus (PEDV), indicating better broad-spectrum antiviral activity than the INTERCAT IFN. As shown in Figure 6 , the purified recombinant feIFN-ωa and feIFN-ωb proteins showed antiviral activity in both homologous animal cells (F81 cells) and heterologous animal cells (Vero, MDCK, MDBK, and PK-15 cells) in vitro. Our data showed that purified recombinant feIFN-ωa and feIFN-ωb had broad-spectrum antiviral activity in homologous and heterologous animal cells, suggesting they are candidates for the development of effective therapeutic agents to be used against viral infections in pet cats.
cord-270498-hh6h50t2	2017	Celastrol-induced heme oxygenase 1 (HO-1) expression promoted antiviral interferon responses and inhibition of NS3/4A protease activity, thereby blocking HCV replication. These antiviral effects were abrogated by treatment with the HO-1-specific inhibitor SnMP or silencing of HO-1 expression by transfection of shRNA, which indicates that HO-1 induction contributes to the anti-HCV activity of celastrol. In this study, our data revealed that celastrol significantly inhibits HCV replication, and that the anti-HCV effect of celastrol was attenuated by the HO-1 specific inhibitor tin mesoporphyrin (SnMP) or HO-1 gene expression silencing. Celastrol-mediated HO-1 induction contributed to the anti-HCV action through inducing antiviral IFN response and inhibiting HCV NS3 protease activity. As shown in Fig. 7B , HO-1 RNA expression levels were induced by celastrol compared with non-celastrol treated cells and the JNK inhibitor SP600125 significantly reduced the HO-1 inductive effect of celastrol. In the present study, we found that a natural product celastrol could effectively inhibit HCV NS3/4A protease activity and enhance IFN-mediated antiviral gene expression through HO-1 induction (Figs.
cord-270534-ebkwv4zo	2018	title: Live-attenuated bivalent measles virus-derived vaccines targeting Middle East respiratory syndrome coronavirus induce robust and multifunctional T cell responses against both viruses in an appropriate mouse model One of these candidates, MV vac2 -MERS-S(H) (Malczyk et al., 2015) , is based on the measles virus (MV) vaccine platform technology (Mühlebach, 2017) , and encodes the MERS-CoV spike protein (S) as an additional antigen in the backbone of recombinant MV vac2 (del Valle et al., 2007) resembling vaccine strain Moraten that is authorized and in use in the US since 1968. (G) Secretion of IFN-γ after antigen-specific re-stimulation of splenocytes harvested 32 days post prime immunization and after co-culture with JAWSII (left) or DC2.4 (middle) dendritic cells transgenic for MERS-N (black) or untransduced controls (NC, white). To assess the capacity of the different MV vac2 -MERS-S(H) vaccine preparations to induce MERS-CoV S-specific cellular immune responses, splenocytes of mice, which had already been tested for humoral responses ( Fig. 2A) , were isolated and analyzed 49 days after immunization for antigen(Ag)-dependent IFN-γ secretion using ELISpot assay.
cord-271114-hv3gwvdi	2015	The objective of this study was to investigate single nucleotide polymorphism (SNP) in the interleukin (IL)-1β –31 T/C, IL-6 –174 G/C, tumor necrosis factor α (TNF-α) –308 G/A, and interferon γ (IFN-γ) +874 A/T genes for their possible association with susceptibility to early onset sepsis (EOS) in Saudi newborn infants. Our results show that the circulating IL-1β, IL-6, TNF-α, and IFN-γ were significantly (p < 0.001) elevated in EOS patients compared to suspected and sepsis-free control groups; and IL-1β –31C, IL-6 –174G, TNF-α –308G, and IFN-γ +874A alleles were associated with EOS in Saudi infants. Therefore, the primary aim of the current study was to investigate SNPs in the IL-1β -31 T/C (rs1143643), IL-6 -174 G/C (rs1800795), TNF-α -308 G/A (rs1800629), and IFN-γ +874 A/T (rs2430561) genes for their possible association with susceptibility to EOS in Saudi newborn infants. Newborns with sepsis had significantly higher serum levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ) compared to both suspected and sepsis-free control groups (overall p value < 0.001, Table 1 ).
cord-271250-ywb26cq6	2019	In-depth understanding of the role of adjuvants in activating the innate immune system, combined with systems vaccinology approaches, have led to the development of next-generation, novel adjuvants that can be used in vaccines against challenging pathogens and in specific target populations. Intact MyD88 signaling in each of the three types of APCs (DCs, macrophages and B cells) is essential for robust activity of TLR ligand-based vaccine adjuvants (PorB, a TLR2 ligand and CpG, a TLR9 ligand) such as induction of in vivo cytokine responses, germinal center (GC) formation and antibody production [49] . A combination adjuvant consisting of poly(I:C), a host defense peptide and PCEP when delivered intranasally transiently induces production of chemokines and cytokines in murine respiratory tissues, which promotes infiltration and activation of DCs, macrophages, and neutrophils to generate improved mucosal and systemic immune responses [55] .
cord-271970-i35pic5o	2020	Depletion of endogenous DDX42 using siRNA or CRISPR/Cas9 knock-out increased HIV-1 infection, both in model cell lines and in physiological targets of HIV-1, primary CD4+ T cells and monocyte-derived macrophages (MDMs), and irrespectively of the IFN treatment. Deep sequencing analysis of the GeCKO cell populations showed more than 94% coverage for both libraries (≥ 10 reads for 61,598 and 54,609 sgRNA-coding sequences out of GeCKO populations were subjected to type 1 IFN treatment in order to induce the antiviral state and, 24h later, incubated with VSV-G-pseudotyped, HIV-1 based LVs coding for an antibiotic resistance cassette. In order to validate the effect of DDX42 KO on HIV-1 infection in another model cell line, two additional sgRNAs were designed (sgRNA-2 and -3) and used in parallel to the one identified in the GeCKO screen (sgDDX42-1) (Figure 2A ).
cord-272117-erzpz3c0	2018	Experimentally, apoptosis of IAV-infected epithelial cells was shown to be dependent upon viral replication, as an inactivated virus failed to induce apoptosis in mice [46] and human cells [47] . PKR can directly sense dsRNA generated during viral replication to induce Fas expression and FADD-dependent apoptosis [52] , as well as inhibit host and viral protein translation through the phosphorylation of eIF2a [53] in IAV-infected cells [54] . Additionally, pandemic and highly virulent strains of the virus, including HPAI and the 1918 H1N1 strain, are known to completely exhaust the replicative niche of epithelial cells of the lung over the course of infection as a by-product of overly exuberant replication and failure of immune response to control viral propagation. Collectively, these findings suggest that in contrast to the biphasic role of epithelial cell apoptosis in preventing or promoting pathogenesis, highly virulent IAV rapidly infects and induces early death in pulmonary M4 to suppress antiviral responses.
cord-272237-gnno6elo	2020	A wearable and deformable graphene-based field-effect transistor biosensor is presented that uses aptamer-modified graphene as the conducting channel, which is capable of the sensitive, consistent and time-resolved detection of cytokines in human biofluids. Based on an ultrathin substrate, the biosensor offers a high level of mechanical durability and consistent sensing responses, while conforming to non-planar surfaces such as the human body and withstanding large deformations (e.g., bending and stretching). Moreover, Tween 80 is used to modify the graphene surface to effectively suppress nonspecific adsorption, thus enabling the biosensor to detect cytokines (TNF-α and IFN-γ, significant inflammatory cytokines, were used as representatives) in artificial tears (used as a biofluid representative). Moreover, Tween 80 is used to modify the graphene surface to effectively suppress nonspecific adsorption, thus enabling the biosensor to detect cytokines (TNF-α and IFN-γ, significant inflammatory cytokines, were used as representatives) in artificial tears (used as a biofluid representative).
cord-272695-wmzq4lkh	2020	This study was undertaken to test the association of TNF-α − 308 and IFN-γ + 874 gene polymorphisms with the susceptibility of Leishmania (L) species among CL patients in central region of Saudi Arabia. The amplified PCR product for TNF-α-308 was detected at 184 base pair as shown in Fig. 1 , based on these results, different species of CL, the genotypes and the alleles of the host genes polymorphism were determined and evaluated in comparison with their respective healthy controls (supplementary file (Table 3 ). The amplified PCR product for IFN-γ + 874 were detected at 263 base pair as shown in Fig. 2 , based on these results, different species of CL, the genotypes and the alleles of the host genes polymorphism were determined and evaluated in comparison with their respective healthy controls.
cord-273050-reez33md	2020	reported that type I interferon (IFN) deficiency, could be a hallmark of severe coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compared with patients that had mild-to-moderate infection, the ISG score (based on the mean expression value of six ISGs defining a type I IFN signature) was significantly reduced in critical patients. By correlated analysis of viral loading with IFN-α production either on protein or on gene level, the authors suggest that the most severe cases of COVID-19 are featured by impaired IFN-α production. To further explore the transcription factors that may cause the excessive inflammatory response of COVID-19, the authors observed that upregulated genes in severe or critical patients mainly belonged to the NF-κB pathway by a kinetic analysis. Impaired type I IFN response featured immunological characteristics of severe COVID-19 patients, accompanied by lymphocytopenia, hypercytokinaemia, and high blood viral load. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients
cord-273122-w9hemznv	2016	
cord-273144-er6irjw3	2012	The availability of genome sequences for other avian species, including the zebrafinch (Warren et al., 2010) , the turkey (Dalloul et al., 2010) and the duck (http://pre.ensembl.org/Anas platyrhyncos/Info/), should allow identification and subsequent characterisation of their immune gene repertoires. Real-time qRT-PCR was used to determine IFN-␥ mRNA expression levels in PHA-stimulated splenocytes (from chicken and turkey) treated with recombinant chicken or turkey IL-10 or mock-transfected COS cell supernatant at various dilutions. Similarly, there was inhibition of IFN-␥ production from PHA-stimulated turkey splenocytes by recombinant chicken and turkey IL-10, although Expression patterns of (A) IL-10 and (B) IL-13 mRNA, as measured by real-time quantitative RT-PCR, in lymphoid tissues, non-lymphoid tissues and digestive tissues of the turkey. At the protein level (72 h post-stimulation), recombinant chicken and turkey IL-10 inhibited the production of IFN-␥ by both chicken and turkey splenocytes at high concentrations, as measured by ELISA, and this effect titrated out with increasing dilution of recombinant IL-10 ( Fig. 3C and D respectively).
cord-274247-5qiwui6u	1999	
cord-274816-6xpma224	2020	Palatine and pharyngeal tonsils are important organs of the immune system, and they protect the body from pathogens invading the upper respiratory tract, especially in young children [8] . In a study on patients with hypertrophic adenoid tissue, recurrent upper and lower respiratory tract infections were demonstrated along with high serum myeloperoxidase levels (indicating neutrophil activation), increased serum eosinophilic cationic protein levels (indicating eosinophil activation) and high CD 163 glycoprotein levels (indicating monocyte/macrophage activation) [15] . It is known that human tonsils are immunologically reactive lymphoid organs carrying out humoral and cellular immunity functions as a response to various antigens and displaying B and T cell activity [16] . In the same study, although a difference was expected in tonsillar hypertrophy and recurrent tonsillitis groups in terms of the levels of interferons (IFN-a, IFN-b, IFN-c, IL-28, IL-29) , which are cytokines with antiviral activity and whose expression is induced by viral infection, not detected.
cord-275413-e2rhioty	2010	The purpose of this study was to characterize the interaction between PRRSV and the pig fetus by (1) identifying sites of virus replication, (2) measuring immune and inflammatory cytokines in different compartments, and (3) evaluating the response of lymph nodes. Maternal, accessory and fetal tissues were collected and stored in formalin for histological staining and immunohistochemistry (IHC), or storage in RNAlater (Ambion) for RT-PCR of cytokine mRNAs. PRRSV-specific antibody was measured in sera using the HerdCheck ® PRRS ELISA (IDEXX) and performed by personnel at Kansas State University Veterinary Diagnostic Laboratory. As shown in Fig. 4A , IFN-␥ and TNF-␣ PCR products were not detected in lung, lymph node or placenta from the non-infected fetuses. To determine if cytokine gene expression was the direct result of PRRSV infection, RT-PCR for IFN-␥ and TNF-␣ was performed on the same tissues from fetuses of infected dam no.
cord-275643-lbikoyo3	2018	The expression of antiviral genes involved in the type I IFN and NF-κB signaling pathways was also downregulated in the presence of HCoV-OC43 structural or accessory proteins. CONCLUSION: Both structural and accessory HCoV-OC43 proteins are able to inhibit antiviral response elements in HEK-293 cells, and to block the activation of different antiviral signaling pathways. Following SeV challenge of HEK-293 cells, the expression of genes involved in the type I IFN and NF-κB signaling pathways was downregulated in the presence of HCoV-OC43 structural or accessory proteins (Fig. 4) . Similar to influenza A NS1 protein, HCoV-OC43 structural (M and N) and accessory (ns2a and ns5a) proteins were able to inhibit the transcriptional activity of antiviral response elements, ISRE, IFN-β promoter, and NF-κB-RE, and to downregulate the expression of several genes involved in the activation of an antiviral response.
cord-275690-83nrzfon	2020	
cord-275795-ee7qyw5h	2018	We focus on immunity generated against both natural infection and vaccination, where a steady shift in conferred vaccination immunogenicity is observed from quantifying activated and proliferating, long-lived effector memory T cell subsets, as the prominent biomarkers of long-term immunity against viruses and their associated disorders causing high morbidity and mortality rates. Since that time, the occurrence of epidemics and outbreaks are now at lower risk, following the introduction of massive vaccination programs able to induce immune system targeting of viruses causing severe disorders affecting distinct geographical locations, and with many epidemiological reports demonstrating long-term efficacy of viral control of non-naïve populations. This approach is being developed to use virus-infected cell-killing antibodies that produce an antiviral environment; these termed antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, which are predicted to link innate and adaptive immune responses, and is becoming possible due to new technologies for rapid isolation and characterization of monoclonal antibodies targeting conserved regions of influenza virus, reviewed in Jegaskanda et al.
cord-276034-a8pixbuc	2005	
cord-276166-b1e0bbrp	2017	Previous studies showed that glycosylated IFN-ω + ribavirin (RBV) had a synergistic effect in terms of its antiviral activity in hepatitis C virus (HCV)-infected patients [43] . [49] showed that interleukin (IL)-6 production was affected considerably in feline immunodeficiency virus (FIV)-infected cats treated with recombinant feline IFN-ω (rFeIFN-ω) by subcutaneous or oral protocols. Because of its antiviral, immunomodulatory, anti-proliferation, and antitumor activities, IFN-ω has been explored as a treatment option for some diseases and viral infections in humans and other animals. Evaluation of viremia, proviral load and cytokine profile in naturally feline immunodeficiency virus infected cats treated with two different protocols of recombinant feline interferon omega Limited efficacy of topical recombinant feline interferon-omega for treatment of cats with acute upper respiratory viral disease Oral recombinant feline interferon-omega as an alternative immune modulation therapy in FIV positive cats: clinical and laboratory evaluation
cord-276350-lcl9jn35	2020	In a mouse model of SARS-CoV infection, local IFN responses in the lungs were delayed relative to peak viral replication, which impeded virus clearance and was associated with the development of CRS 5 . By contrast, IFNAR inhibition enhanced the recruitment of neutrophils to the lungs in MERS-CoV-infected mice, leading to elevated production of pro-inflammatory cytokines 6 . While patients with severe COVID-19 showed profound depletion and functional exhaustion of NK cells 8 , it is unclear whether this NK cell dysfunction is due to dysregulation of IFN responses. It is thus tempting to speculate that the deficient or dysregulated IFN responses elicited by SARS-CoV-2 infection may influence the generation of T reg cells during the recovery phase of COVID-19. Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice
cord-276587-ynionj5r	2018	
cord-277409-q5wx313k	2016	Additionally, LbSap has been shown to induce a prominent pro-inflammatory immune response characterized by increased levels of both IL-12 and IFN-γ and decreased levels of TGF-β by peripheral blood mononuclear cells (PBMCs), which were associated with parasite control in dogs [26] . Previous studies of dogs using the "LbSapSal" vaccine displayed higher counts of circulating and Leishmania-specific CD8 + T cells in addition to high nitric oxide (NO) production [22] and reduction of splenic parasite load [27] . chagasi-challenge (T 90) demonstrated that "LbSapSal" group showed a significant increase of TNF-α levels (P<0.05) upon VSA-stimulation as compared to "Sal" and "LbSal" groups ( Fig 1A, middle panel) . The results observed at the post-vaccination period (T 3rd ) demonstrated that the "LbSal" group showed a significant reduction in the IL-10 levels (P<0.05) upon VSA-stimulation as compared to the "Sal" group ( Fig 2B, middle panel) .
cord-277487-jgbjxgh1	2020	Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunisation enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralising titres. Analysis of SARS-CoV-2 S protein-specific murine splenocyte responses by IFNγ ELISpot assay showed no statistically significant difference between the prime-only and primeboost vaccination regimens, in either strain of mouse ( Figure 1A ). IFN-γ ELISpot analysis of porcine peripheral blood mononuclear cells (PBMC) showed responses on 42 dpv (2 weeks after boost) that were significantly greater in the prime-boost pigs compared to prime-only animals (p < 0.05; Figure 1C ). : SARS-CoV-2 S protein-specific antibody responses following ChAdOx1 nCoV-19 primeonly and prime-boost vaccination regimens in mice and pigs.
cord-278018-3qemb0x3	2011	
cord-278050-wl83d6gs	2005	
cord-278159-afce61g0	2013	
cord-278397-u33x4jaw	2018	Recent efforts have focused on identifying relevant immune surveillance sensors and components of downstream signaling-Toll-like receptors (TLRs) and their cognate ligands, cytosolic sensing of RNA (primary mediated by the RIG-I/IPS-1 axis), cytosolic sensing of DNA (primary mediated by the cGAS/STING axis), and the inflammasome pathway (primary mediated by NOD-like receptors; NLRs) (Broz and Monack, 2013; Kieser and Kagan, 2017; Kumar et al., 2011a ). It has also been suggested that chronic cGAS/STING activation induced by self DNA may be responsible for induction of aberrant inflammatory diseases like systemic lupus erythematosus (SLE), Aicardi-Goutières syndrome (AGS), and polyarthritis (Barber, 2015; Crowl et al., 2017) . Use of DNA damage induced agents like 7,12-dimethylbenz-α-anthracene (DMBA) has helped shed light on the underlying events initiate the DNA damage-induced immune response via cytosolic DNA sensing pathway and implicates nucleosome leakage in eliciting cGAS/STING-dependent signal activation via recognition of self-DNA (Barber, 2015) .
cord-278523-djjtgbh6	2020	
cord-278569-yr06jwm1	2012	
cord-278577-bx86tq0y	2018	We investigated the differences in virus detection and T cell and interferon gene expression in patients undergoing tonsillectomy due to tonsillar hypertrophy or recurrent tonsillitis. However, data are scarce on the differences in tonsillar virus infections and immune responses between patients with tonsillar hypertrophy or recurrent tonsillitis [6] [7] [8] . Therefore, we studied whether virus detection and T cell and interferon gene expressions differed between the two main indications of surgery, tonsillar hypertrophy or recurrent tonsillitis. The adjustments for immunologic analyses were chosen using backward stepwise multivariable models that initially included clinical factors and virus infections which significantly differed between the groups (age, self-reported pollen allergy, self-smoking, both adenotomy and tonsillectomy performed, respiratory symptoms one month prior to the operation and bioavailable 25(OH)D level). This study shows differences in virus detections and T cell and interferon gene expressions in patients undergoing tonsillectomy due to tonsillar hypertrophy or recurrent tonsillitis.
cord-278648-hkvurb2k	2017	While the absence of 2′O-MTase activity had only a marginal impact on propagation and replication in Vero cells, dNSP16 mutant MERS-CoV demonstrated significant attenuation relative to the control both in primary human airway cell cultures and in vivo. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Generation of mutants with changes in the NSP16 KDKE active site resulted in IFN-mediated in vitro and in vivo attenuation of both mouse hepatitis virus (MHV) and SARS-CoV (9, 10) . While a more rapid CPE following both WT and dNSP16 mutant MERS-CoV infections precluded an equivalent finding at late time points, the SARS-CoV results suggest that the absence of NSP16 activity eventually initiates host response changes that contribute to attenuation at late time points.
cord-279725-d82sj80v	2004	We evaluated the susceptibility of the SARS-related coronavirus (SARS CoV) to ribavirin and interferon (IFN)-α in vitro by use of cytopathic effect, plaque assay, and immunoblot analysis. To support the search for effective antiviral treatments, we evaluated the susceptibility of SARS CoV isolates (detailed studies were performed with the Tor2 isolate [Toronto, Canada]) to ribavirin and interferon (IFN)-a-2b in vitro. Our data indicate that ribavirin does not inhibit the virus at concentrations attainable in human serum but that IFN-a-2b may be useful and deserves further evaluation as a therapeutic agent. To quantify the effect of IFN-a-2b on the replication of the SARS CoV, Vero E6 cells were infected at an MOI of 0.001 and were incubated in the presence IFN-a-2b (0-5000 IU/mL), as described above. Whether combined therapy with IFN-a-2b and ribavirin would inhibit the replication of the SARS CoV in vitro has not yet been evaluated; the combination is more effective than either agent used alone for the treatment of HCV infection in humans.
cord-279733-c0w9bw5u	2016	title: Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3 Collectively, our findings suggest a common and conserved mechanism through which highly pathogenic MERS-CoV and SARS-CoV harness their M proteins to suppress type I IFN expression at the level of TBK1-dependent phosphorylation and activation of IRF3 resulting in evasion of the host innate antiviral response. In non-specialized epithelial cells as well as a subset of specialized immune cells that are susceptible to MERS-CoV infection, 16, 18, 27 type I IFN production is an important part of the host innate immune response and is initiated by ubiquitously expressed cytoplasmic viral sensors in the retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) family in response to the detection of viral pathogen-associated molecular patterns such as double-stranded RNA (dsRNA). Middle east respiratory syndrome coronavirus 4a protein is a double-stranded RNA-binding protein that suppresses PACT-induced activation of RIG-I and MDA5 in the innate antiviral response
cord-279781-5ldpz9m9	2011	Concurrent with the aforementioned findings, we also discovered that baculovirus transduction of human BMSCs disturbed the expression of 816 genes, most of which were related to 5 signaling pathways: cell adhesion molecules, TLR, Jak-STAT, apoptosis as well as antigen processing and presentation (Chen et al., 2009b) . immunization of chickens with another VSVG-pseudotyped baculovirus expressing HA of H5N1 avian influenza virus (AIV) also evoked significantly higher levels of H5-specific antibody and cellular immunity than those receiving DNA vaccines, and conferred protection against lethal challenge with the homologous virus strain (Wu et al., 2009b) . Transient and stable gene expression in mammalian cells transduced with a recombinant baculovirus vector Baculovirus as a highly efficient gene delivery vector for the expression of hepatitis delta virus antigens in mammalian cells
cord-279924-09uwhxs9	2014	In this study, we demonstrate that cultured murine NPCs are infected by the neurotropic JHM strain of mouse hepatitis virus (JHMV), which induces acute encephalomyelitis and chronic demyelination when injected intracranially into immunocompetent mice. We co-cultured virus-specific CTLs at diminishing effectorto-target (E:T) ratios with NPCs pulsed with the immunodominant CD8 peptide specific for JHMV spike (S) glycoprotein spanning amino acids 510-518 (S510-518), and treated with IFN-γ to induce MHC class I expression. To confirm the role of IFN-γ as the major cytokine contributing to suppression of JHMV replication in infected NPC cultures, monoclonal antibody blockade against the IFN-γ receptor was performed on NPCs before and during treatment with virusspecific CD4þ T cell enriched media. Impaired expression of MHC class II following IFN-γ-treatment of infected NPCs may be a mechanism employed to subvert detection by infiltrating virus-specific CD4þ T cells.
cord-280005-i9fp5rys	2020	title: Treatment of COVID-19 Patients with Prolonged Post-Symptomatic Viral Shedding with Leflunomide -a Single-Center, Randomized, Controlled Clinical Trial CONCLUSIONS: In COVID-19 patients with prolonged PCR positivity, no benefit in terms of the duration of viral shedding was observed with the combined treatment of leflunomide and IFN α-2a beyond IFN α-2a alone. Based on that background, we conducted a prospective randomized, controlled, open-label trial, to evaluate the efficacy and safety of oral leflunomide to treat hospitalized COVID-19 patients with prolonged post-symptomatic viral shedding. Fifty eligible patients were randomly assigned to a combination treatment group that received leflunomide (50 mg, q12h, three consecutive times, orally; then 20 mg, once a day for 8 days; a total course of 10 days) plus nebulized IFN -2a (3 million IU each time, adding 2 ml of sterilized water, atomization inhalation twice daily for 10 days), or to a control group that received nebulized IFN -2a This was an open-label, prospective randomized, controlled trial, which was conducted at East Campus, Renmin Hospital of Wuhan University.
cord-280130-ewqe9edq	2007	In most nucleated body cells, viral infections activate transcription of the ''''classic'''' IFN-b gene [1] by a signaling chain which is initiated by the RNA sensors RIG-I and MDA-5, which in turn act trough the adaptor IPS-1 and the kinases TBK-1 and IKK-3 to activate the transcription factor IRF-3 (see reviews by P. Many RNA and DNA viruses therefore express proteins which bind this key molecule to avoid both IFN induction and activation of dsRNA-dependent antiviral enzymes [7, 8] . Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the elF-2 translation initiation factor Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling Double-stranded RNA binding of influenza B virus nonstructural NS1 protein inhibits protein kinase R but is not essential to antagonize production of alpha/beta interferon
cord-280960-88hzovg2	2020	
cord-282242-5tkhjiwl	2009	
cord-282246-wyanwvxa	2020	
cord-282395-uwxk1o6d	2016	
cord-282947-3hgku2e4	2017	title: Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3 Through the construction of recombinant IBV expressing proteins 8a, 8b and 8ab encoded by SARS-CoV ORF8, we demonstrate that expression of 8b and 8ab enables the corresponding recombinant viruses to partially overcome the inhibitory actions of IFN activation to achieve higher replication efficiencies in cells. Compared to wild type and rIBV8a/b, however, rIBV8b and rIBV8ab were observed to replicate significantly better and express higher levels of N protein in cells stimulated by poly (I:C) (Fig. 2a) . In view of the central role of IRF3 in regulating IFN activation during virus infection, 8b and 8ab with Flag epitope-tagged to their Ntermini were co-expressed with Myc-tagged IRF3 (Fig. 3a) in Cos-7 cells using the vaccinia/T7 expression system (Anderson et al., 1996; Lim and Liu, 2001) for co-immunoprecipitation assays to determine if there is any physical interaction between the proteins.
cord-283096-qm7h4qui	2010	Some of them are type I IFN-induced proteins, such as PKR and RIG-I, and some are the key regulators that are involved in IFN signaling, such as JAK1 and STAT1, implicating the role of ISG15 and its conjugates in type I IFN-mediated innate immune responses. Viral infection also strongly induces ISG15 [18, 19] because one of its major host responses is the production of type I IFNs. A number of proteins that are involved in antiviral signaling pathways, including RIG-I, MDA-5, Mx1, PKR, STAT1, and JAK1, have been identified as target proteins for ISGylation. Swiss 3T3 cells expressing constitutively active MKK7-JNK1β fusion protein show increased resistance to apoptosis induced by vesicular stomatitis virus (VSV) infection, suggesting the involvement of JNK signaling pathway in antiviral response. acid seems to elevate the levels of ISG15 and its conjugates by stimulating cells to secrete IFNs. UBE1L is a 112-kDa protein that shows a 45% identity in amino acid sequence to the human ubiquitin-activating E1 enzyme (UBE1) [73] .
cord-283505-ousbar6c	2020	To elucidate the cellular immune mechanisms associated with disease severity and progression, we used a ferret model to closely resemble disease outcomes in humans following influenza virus infection. In this study, we aimed to examine the ferret immune response to H7N9 influenza virus infection by analyzing leukocyte population variation associated with disease pathogenesis. While the day 6 ferret which showed worsened disease progression did exhibit the most severe lung pathology, the lack of viral antigen in and around these lesions (Supplementary Figure 1) means they cannot conclusively be classified as being caused by the influenza infection, and thus we are hesitant to classify disease presentation in this ferret as like a high pathogenicity infection based on the histopathology findings regardless of the increase in clinical signs. Highly pathogenic avian influenza virus infection in chickens but not ducks is associated with elevated host immune and pro-inflammatory responses
cord-285148-bch7814v	2012	However in vitro RV infection of epithelial cells from COPD patients resulted in higher virus load and increased inflammatory mediators, but no differences in interferon production compared to cells from control subjects [87] . List of abbreviations ATF: activating transcription factor; BAL: bronchoalveolar lavage; CF: cystic fibrosis; CFTR: cystic fibrosis transmembrane regulator; COPD: chronic obstructive pulmonary disease; ENA-78: epithelial-derived neutrophilactivating peptide 78; ICAM-1: intercellular adhesion molecule; IFN-α: interferon-alpha; IFN-β: interferon-beta; IFN-λ: interferon-lambda; IFN-γ: interferon-gamma; IL: interleukin; IP-10: IFN-γ-induced protein-10; IRF: interferon regulatory factor; ISG: interferon stimulated genes; MDA-5: melanoma differentiation-associated protein-5; NF-κB: nuclear factor-kappa B; NO: nitric oxide; NOS2: nitric oxide synthase 2; PCR: polymerase chain reaction; PEF: peak expiratory flow; PIV: parainfluenza virus; RANTES: regulated on activation: normal T-cell expressed and secreted; RIG-I: retinoic acid inducible gene I; RSV: respiratory syncytial virus; RV: rhinovirus; SLPI: secretory leukoprotease inhibitor; SOCS: suppressor of cytokine signaling family; Th1/2: T helper 1/2; TLR: toll-like receptors; TNF-α: tumor necrosis factor-alpha -1.
cord-285744-jpw8hen9	2009	Aim: To determine whether nasopharyngeal aspirates (NPAs) cytokine response is different according to the causative viruses in children with lower respiratory tract infections (LRTI). Several studies (1-3) have investigated cytokine profiles in nasopharyngeal aspirates (NPAs) during viral lower respiratory tract infections (LRTI) in children. Previous studies (1, 3) were demonstrated that patients with respiratory syncytial virus (RSV) infection and those with influenza virus infection induce different cytokine profiles. The present study was performed to determine whether clinical responses in children with LRTI would differ according to causative viruses and to examine the differential patterns of IL-4, IL-5 and IFN-γ concentrations in NPA during acute viral lower respiratory infections according to the causative organisms. The present study of viral LRTI children indicated that as seen in NPAs local inflammatory cytokine responses differed according to the causative organisms.
cord-285757-fiqx4tll	1999	To study whether MxA protein expression is systemically upregulated during rhinovirus infection, blood specimens were collected from 40 patients with common cold and MxA expression in mononuclear cells analyzed by flow cytometry. In conclusion, expression of MxA in blood lymphocytes and an apparently systemic type I interferon response is not induced during rhinovirus infection or during most other cases of common cold in young adult patients. In the present study, the induction of a systemic IFN response as reflected by the expression of MxA protein in blood lymphocytes of patients with rhinovirus infection was examined. Our data suggests that type I IFN production in serum is not comparable to that seen in most other respiratory viral infections in vivo, since the rhinovirus-positive patients had only low or no expression of the MxA protein and no IFN-a/b was detectable in serum samples.
cord-286072-kgpvdb42	2020	While awaiting the results of the many clinical trials that are evaluating the efficacy of IFN-I alone or in combination with antiviral molecules, we discuss the potential benefits of a well-timed IFN-I treatment and propose strategies to boost pDC-mediated IFN responses during the early stages of viral infection. IFN, interferon; IFNAR, interferon alpha and beta receptor; IκB, inhibitor of nuclear factor κB; IKKε, IκB kinase-ε; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; JAK, Janus kinase; M, membrane; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated gene 5; N, nucleocapsid; Nsp, nonstructural protein; ORF, open reading frame; P, phosphate; PLP, papain-like protease; RIG-I, retinoic acid-inducible gene 1; SARS-CoV, severe acute respiratory syndrome coronavirus; STAT, signal transducer and activator of transcription; TANK, TRAF family member associated NF-κB activator; TBK1, TANK-binding kinase 1; TRAF3, tumor necrosis factor receptor-associated factor 3; TYK2, tyrosine kinase 2.
cord-286328-ap0wfjhq	2012	CONCLUSIONS & CLINICAL RELEVANCE: We conclude that, in children with asthma, naturally-occurring viral infections apparently induce a robust innate immune response including expression of specific chemokines, IFNs and IFN-responsive genes. To further examine the innate immune response to viral infection in children with asthma, we measured nasal aspirate cytokine levels in 16 asthmatic children before and after upper respiratory tract infections. We also examined the effects of upper respiratory tract infection on mRNA levels of selected markers of viral infection, including IFNs. Finally, we evaluated a new method of virus detection using a single polymerase chain reaction-ligation detection reaction (PCR-LDR) multiplex assay. We performed home measurements of respiratory symptoms and collected nasal secretions (for detection of viral RNA by PCR and host biomarkers by PCR and ELISA) on 3 days during a week when children were healthy (not reporting upper respiratory tract infection or asthma symptoms), and again during a week when they experienced cold or flu-like symptoms.
cord-286824-3e534pws	1999	
cord-287018-g4y5kjju	2006	In order to solve this durability problem, we tested DNA constructs encoding virus-specific long-hairpin RNAs (lhRNAs) for their ability to inhibit HIV-1 production. The lhRNA constructs were compared with in vitro diced double-stranded RNA and a DNA construct encoding an effective nef-specific shRNA for their ability to inhibit HIV-1 production in cells. For this reason, the DNA constructs encoding lhRNAs (a single-hairpin molecule) and long dsRNAs (two complementary molecules that form a duplex) were designed to target tat, rev and nef sequences as indicated in Figure 1 . 21 nef2 dsRNA induced a decrease in luciferase expression, but an even more pronounced level of inhibition was Figure 1 Scheme of the human immunodeficiency virus type 1 (HIV-1) pLAI proviral genome and target sequences used for the design of long-hairpin RNAs (lhRNAs).
cord-287874-wl0wlxh6	2020	From 31 January 2020 to 10 February 2020, the patient was given quadruple therapy, including lopinavir/ritonavir tablets (400/100 mg every 12 h), arbidol tablets (0.2 g every 8 h), Lianhuaqingwen granules (a Chinese patent medicine, 6 g every 8 h) orally, and recombinant human interferon-α2b injection via aerosol (6.0 × 10 6 IU with 2 ml of sterilized water for injection every 12 h). • Quadruple therapy, which is lopinavir/ritonavir tablets, arbidol tablets, Lianhuaqingwen granules, and recombinant human interferon-α2b (IFN-α2b) injection via aerosol, is a common regimen for patients with COVID-19 in China. From 31 January 2020 to 10 February 2020, the patient was treated with four drugs, which are oral administration of lopinavir/ritonavir tablets (400/100 mg every 12 h), arbidol tablets (0.2 g every 8 h), and Lianhuaqingwen granules (a Chinese patent medicine, 6 g every 8 h) and atomization inhalation of recombinant human interferon-α2b injection (6.0 × 10 6 IU with 2 ml of sterilized water for injection every 12 h).
cord-288017-f9b3t0ts	2020	High risks for fatal disease in COVID‐19 include older age, metabolic syndrome, male gender, and individuals who develop delayed type I IFN response. 54 In a macaque model of SARS-CoV infection too, aged macaques had more severe lung pathology, lower expression of type I IFN and higher expression of pro-inflammatory cytokines as compared to younger macaques. 80 to patients with COVID-19 that it is a mild immunomodulatory F I G U R E 2 Hydroxychloroquine (HCQ) inhibits SARS-CoV-2 entry and inhibits virus-induced type I interferon (IFN) signaling and proinflammatory cytokines production. While male gender, older age and people with metabolic syndrome seem to be at a higher risk of contracting more severe SARS-CoV-2 infection, younger females of African and Asian ancestry have higher risk for developing SLE; male gender among lupus patients, however, is an independent risk factor for severe disease. Evasion by stealth: inefficient immune activation underlies poor T cell response and severe disease in SARS-CoV-infected mice
cord-288238-36hiiw91	2020	It is also reported that influenza infection significantly increases ROS production by inducing Nox4, and the proliferation of this virus in lung epithelial cells is dependent on redox-sensitive pathways activated by Nox4-derived ROS [16] . IFN can also exert its function on metabolic changes by producing several mediators including indoleamine-2,3-dioxygenase (IDO) and nitric oxide (NO), both of which appear to have either an inducible or an inhibitory role in viral replication [33] . In addition, increased temperature of cells during infection (which could be the result of virus replication and fever) causes heat stress which in turn can considerably downregulate carnitine palmitoyltransferase II (CPT II) activity and reduce the β-oxidation and ATP levels in fibroblasts of influenza-associated encephalopathy patients and healthy volunteers [110] . Through enhancing the activity of the mTORC1 complex, the influenza virus strengthens several metabolic pathways, including glycolysis, glutaminolysis, pentose phosphate, and fatty acid synthesis, to provide more ATP and structural materials for viral replication.
cord-288960-v6l6o5va	2017	Possibly via RIG-I -dependent RNA detection which may in turn induce STING [6] Vesicular stomatitis virus Negative strand ssRNA virus Unknown [6] Human immunodeficiency virus Negative strand ssRNA virus dsDNA reverse transcribed from viral RNA induces cGAS-STING pathway [28] Influenza A virus Negative strand ssRNA virus Possibly via membrane fusion or unknown mechanism independent of DNA recognition [29] Mycobacteria tuberculosis Bacteria producing c-di-GMP c-di-GMP [30, 31] Streptococcus pneumoniae Bacteria dsDNA Bacterial dsDNA [32] Streptococcus pyrogenes Bacteria dsDNA Bacterial dsDNA [33] Staphylococcus aureus Bacteria producing c-di-AMP c-di-AMP [34] Listeria monocytogenes Bacteria producing c-di-AMP c-di-AMP [35] Vibrio cholera Bacteria producing 3′-3′ cGAMP 3′-3′ cGAMP [36, 37] Abbreviations: dsDNA double-stranded DNA, ssRNA single-stranded RNA The type I interferon signal adaptor protein STING is responsible for mediating double-stranded DNA sensing responses and the detection of bacterial cyclic dinucleotides c-di-AMP, c-di-GMP, and 3′-3′ cGAMP.
cord-289101-ko1knslk	2020	Our previous clinical pilot study indicated that aerosol inhalation of IFN-k plus TFF2 is a safe treatment and is able to significantly facilitate clinical improvement, including cough relief, CT imaging improvement, and viral RNA reversion, thereby resulting in an early release from hospitalization without induction of a proinflammatory response [20] . This study demonstrated that the combination inhalation of IFN-k and TFF2 is able to shorten the time of viral RNA negative conversion and CT improvement, and facilitating patients early discharge from the hospital, in the absence of induction of a proinflammatory response and treatment-related adverse events. The primary endpoint was a significantly shorter time (Mean 3¢80 days, 95% CI 2¢07À5¢53) from the start of the study treatment to viral RNA negative conversion for SARS-CoV-2 in all clinical samples, including nasopharyngeal swabs, throat swabs and stool swabs, in experimental group than in control group (7¢40 days, 95% CI 4¢57À10¢23) (p = 0¢031), and difference between means was 3¢60 days (Fig. 2A) .
cord-289413-mbrw85og	2019	
cord-290396-cy4y8vnt	2004	title: Innate immunity in the retina: Toll-like receptor (TLR) signaling in human retinal pigment epithelial cells We evaluated the expression and function of TLRs in human retinal pigment epithelial (RPE) cells. The presence of TLRs on RPE cells and the resultant TLR signaling in RPE cells suggest that these molecules may play an important role in innate and adaptive immune responses within the retina. Our data suggest that the binding of poly I:C, an analog of dsRNA, to TLR 3 on human RPE cells resulted in the production of IFN-h and other cytokines, chemokines, and adhesion molecules. Total RNA prepared from confluent monolayers of human RPE cells and from suspension cultures of U937 was used to evaluate the constitutive expression of TLR mRNA. To study the effects of TLR activators, human RPE cells were washed with serum-free media (SFM) and incubated in SFM for 12 h in the presence of poly I:C (100 Ag/ml ), LPS (5 Ag/ml), or IFN-g (100 U/ml).
cord-290593-vhmi2559	2012	title: Interplay of foot-and-mouth disease virus, antibodies and plasmacytoid dendritic cells: virus opsonization under non-neutralizing conditions results in enhanced interferon-alpha responses Vaccine-induced immune protection correlates with the presence of high levels of neutralizing antibodies but also opsonising antibodies have been proposed as an important mechanism of the immune response contributing to virus clearance by macrophages and leading to the production of type-I interferon (IFN) by plasmacytoid dendritic cells (pDC). The present study demonstrates that the opsonising antibody titres mediating enhanced IFN-α responses in pDC were similar to neutralizing titres, when antigenically related viruses from the same serotype were employed. Considering the possible importance of opsonising antibodies and pDC in the protection against FMDV, the main aim of this study was to characterize the relationship between neutralizing and opsonising activities of polyclonal sera from immunized pigs. Plasmacytoid dendritic cell activation by foot-and-mouth disease virus requires immune complexes
cord-290744-m0vpizuh	2016	
cord-292289-amzzdh3t	1994	Compared with each virus control culture of fcwf-4 cells, yields of rotavirus, feline panleukopenia virus (FPLV), feline calicivirus and feline infectious peritonitis coronavirus were reduced by ranges of 1.3 to ⩽3.1 log10, 0.6 log2, 0.8 to 3.7 log10 and 0.5 to 0.6 log10, respectively, in the cultures continuously treated with 10 to 10000 U of the rFeIFN. Preformed monolayers of fcwf-4, CRFK or MDCK cells in 24-well cell culture plates (Coming, New York) were treated with the rFelFN at 37°C for 24 h before challenge of VSV, FHV, rotavirus, FIPV and FCV. (2) FPLV Growth of the TU 1 strain in both fcwf-4 and CRFK cell cultures was slightly but IFN dose-dependently inhibited when the cells were continuously treated with the rFelFN for 96 h (Table 1) . The results indicate that certain degrees of antiviral effects against rotavirus, FIPV, FCV and FPLV can be generated in the feline cells by treatment with the rFelFN.
cord-292593-apdyaujt	1985	Interference with vesicular stomatitis virus (VSV) production by JHMV was tested in persistently or latently infected RN-2 cells using as the controls, uninfected RN2-2 cells. Since upon infection of RN2-2 cultures with JHMV at 39.5"C and maintenance in a state of latency at that temperature for several days, the cells commenced yielding pfu upon shift down to 32.5"C (Lucas et al., 1978) , these data suggest that penetration and eclipse of the virus inoculum must have occurred normally at 39.5"C and restriction most probably developed at a subsequent stage. It is very significant that during incubation at the restrictive temperature for as long as 7 days and beyond, when RN2-2 cells had multiplied through 6-7 generations, the 56K antigen was readily detectable (channel I), implying that during latency, in the absence of infectious virus production, translation into JHMV nucleocapsid protein continued.
cord-294125-v2dr4hm0	2018	Finally, based on our recent observations, we discuss the essential functions of mitochondria in the antiviral response and examine the role of ISG15 in the regulation of mitochondrial processes, specifically OXPHOS and mitophagy. Binding to IFNARs leads to the activation of the Janus kinase-signal transducer and activator of transcription proteins (JAK-STAT) signaling pathway and the formation of the interferon-stimulated gene factor 3 (ISGF3) complex, with the subsequent expression of IFN-stimulated genes [3] that establish an antiviral state and play important roles in determining the host innate and adaptive immune responses [4] . In the following sections, we discuss the antiviral mechanisms mediated by ISGylation of both viral and cellular proteins, with a focus on mitochondrial proteins, as we recently showed that ISG15 modulates essential mitochondrial metabolic processes such as respiration and mitophagy in macrophages, with important implications for innate immune responses [29] .
cord-295508-yhdj5m0e	2006	
cord-295684-d3p9nbgq	2011	Experiments showed that similar to their human counterparts, mIFN-λ2 and mIFN-λ3 signal through the IFN-λ receptor complex, activate ISGF3, and are capable of inducing antiviral protection and MHC class I antigen expression in several cell types. IFN-α immunoregulatory functions include major histocompatibility complex (MHC) class I expression in normal and tumor cells, activation of NK cells, dendritic cells (DCs), and macrophages, resulting in the promotion of adaptive immune responses against tumors and virally infected cells [19, 20] . The secretion of constant amounts of various cytokines by transduced tumor cells at the site of tumor growth could elicit more To investigate the potential antitumoral role of IFNλ, we first evaluated the response of B16 melanoma cells to IFN-λ, by analyzing STAT1 activation and MHC class I antigen expression.
cord-295781-b831y105	2017	title: Lung epithelial cells have virus-specific and shared gene expression responses to infection by diverse respiratory viruses We used microarray analysis to compare changes in gene expression of murine lung epithelial cells infected individually by three respiratory viruses causing mild (rhinovirus, RV1B), moderate (coronavirus, MHV-1), and severe (influenza A virus, PR8) disease in mice. While these models are invaluable for evaluating pathology and host responses to infection, parallel in vitro studies can be used to identify gene expression and signaling pathway changes that occur in infected cells to mediate pathogenesis. In this study, we compare the gene expression response of murine lung epithelial cells to infection by three respiratory viruses used in murine models: rhinovirus (serotype RV1B) in the family Picornaviridae, mouse hepatitis virus (MHV strain 1) in the family Coronaviridae, and influenza A virus (strain PR8) in the family Orthomyxoviridae.
cord-296033-5zyoddl7	2017	Coronaviruses (CoVs), such as human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome CoV (SARS-CoV), murine hepatitis virus (MHV), porcine epidemic diarrhea virus (PEDV), and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), encode papain-like (PL) proteases that inhibit Sendai virus(SeV-) induced interferon (IFN-β) production. Furthermore, TGEV PL1 exerted deubiquitinase (DUB) activity which strongly inhibited the retinoic acid-induced gene I(RIG-1-) and stimulator of interferon gene(STING-) dependent IFN expression. In the present study, we found that TGEV PL1 encoded by the replicase gene could suppress the IFN-expression and inhibit the nuclear translocation of interferon regulatory factor 3 (IRF3) and exerted deubiquitinase (DUB) activity which strongly inhibited the retinoic acid-induced gene I-(RIG-1-) and stimulator of interferon gene-(STING-) dependent IFN expression. We observed the inhibition of SeV-induced IFN-promoter activation in the presence of PL1, similar to the antagonistic function of NL63 PLP2 and porcine epidemic diarrhea virus (PEDV) PLP2, clearly indicating that TGEV PL1 could act as an interferon antagonist.
cord-296441-682uop9z	2017	Swine IV infection induced interferon (IFN)-alpha and interleukin-6 responses in bronchoalveolar fluids (BALF) at day 3 post infection, as opposed to the other non-swine-adapted virus strains. Swine IV infection induced interferon (IFN)-alpha and interleukin-6 responses in bronchoalveolar fluids (BALF) at day 3 post infection, as opposed to the other nonswine-adapted virus strains. In order to answer these questions, samples from pigs infected with a Swine (H3N2) and four different non-swine-adapted H3N8 IV strains circulating in different animal species (dogs, horses, wild aquatic birds, and seals) from our previous study (16) were analyzed and innate immune responses in the respiratory tract were thoroughly investigated. In order to check IV replication in the lower respiratory tract of pigs, BALF samples collected from pigs killed at day 3, 6, and 21 were tested for gene M of the influenza A virus using a quantitative real-time PCR procedure (17) .
cord-296948-sqxrwgif	2016	
cord-297512-l9re9h4j	2011	
cord-297712-yy4g5npi	2016	Here, we demonstrate that nonstructural protein 5 (nsp5) of PDCoV, the 3C-like protease, significantly inhibits Sendai virus (SEV)-induced IFN-β production by targeting the NF-κB essential modulator (NEMO), confirmed by the diminished function of NEMO cleaved by PDCoV. A study published by our lab also demonstrated that nsp5, the 3C-like protease of porcine epidemic diarrhea virus (PEDV), which is classified into the Alphacoronavirus family, antagonizes IFN-β production by cleavage of NEMO . In this study, we reveal that nsp5 of PDCoV antagonizes the type I IFN signaling pathway through the cleavage of NEMO, a critical constituent of the IKK complex, thus representing a newly identified mechanism by which PDCoV evades the innate immune response. In contrast, TBK1induced activation of the IFN-β promoter was not affected by nsp5 (Fig. 3A) , suggesting that PDCoV nsp5 inhibits RIG-I/MDA5 signaling by targeting NEMO or other upstream proteins.
cord-297776-k38jssr0	2020	gene expression, we report significant transcriptional upregulation of multiple genes associated with activation of ER sensors IRE1, ATF6, and PERK, such as Edem1, Hspa5 (encoding BiP protein), and Ddit3 (encoding CHOP), in response to virus replication, with the most robust response detected in cells infected with the wild-type or DUBmut virus infection (Fig. 5B, C, and D) . Overall, these differential gene expression analyses in macrophages reveal similar host responses to the wild-type and DUBmut viruses that include activation of UPR pathways and proinflammatory genes, whereas a distinct transcriptional profile during infection with the EndoUmut virus is predominately defined by a focused, robust antiviral response. The results presented here, and from studies of the MERS-CoV dORF3-5 mutant virus (26) Upon infection of a BMDM with EndoUmut, host double-stranded RNA (dsRNA) sensors (including MDA5, PKR, and OAS) are activated, resulting in robust transcription of type I IFN genes and rapid induction of apoptosis, the latter of which precludes the development of a potent inflammatory response.
cord-297790-tpjxt0w5	2018	Among them are filoviruses (e.g., Marburg, Ebola), coronaviruses (e.g., SARS, MERS), henipaviruses (e.g., Hendra, Nipah) which share the common features that they are all RNA viruses, and that a dysregulated immune response is an important contributor to the tissue damage and hence pathogenicity that results from infection in humans. It is likely that differences in evolutionary history of pathogen exposure between bats and humans have led to distinct adaptations in anti-viral immune responses and the ability to tolerate certain infections without disease while being susceptible to others. We summarize this work below, but comparisons of observations made across species suggest that although a number of species appear to be capable of avoiding the pathological effects of RNA virus infection, each bat species may have achieved this through distinct pathways, possibly involving changes to both increase pathogen replication control and to mitigate any immunopathology through decreased inflammatory responses and hence increased disease tolerance.
cord-298131-zolwjl9u	2010	
cord-298259-r9rn0yyz	2008	To investigate the function of type I IFNs upon viral infection in bats, the nucleic acid, and amino acid sequences of Egyptian Rousette (Rousettus aegyptiacus) IFN-α and -β were characterized. Stimulation of bat primary kidney cells (BPKCs) and bat lung cell lines, Tb-1 Lu, with polyinosinic–polycytidylic acid (poly(I:C)) or exogenous bat type I IFNs resulted in increased type I IFNs mRNA expression in BPKCs, but not in Tb-1 Lu. Characterization of the bat IFN-α and -β genes allows understanding of the immune responses upon stimulation in different tissues, thus providing practical strategies for control and treatment of clinically important diseases. These results are important especially for the virus infection, and suggest that future molecular studies on virus infection experiment of bats in vitro will require careful consideration of the differences of type I IFN expression patterns in different cell types. These data suggested that Ebola virus might evade the anti-viral activity of IFNs in bat cells.
cord-298938-xemarhlv	2004	
cord-299299-ov6bf1ff	2015	Replication of BTV8(H) was relatively poor in interferon (IFN)-competent primary ovine endothelial cells compared to replication of BTV8(L), and this phenotype was determined by several viral genomic segments, including Seg4 and Seg9. Here, in order to determine the roles played by specific BTV genomic segments in virus adaptation to tissue culture and attenuation in vivo, we compared genetic and phenotypic differences between BTV8 NET2006 minimally passaged in tissue culture, a derivative of this strain extensively passaged in cell culture, and 34 reassortants between the two viruses. Both viruses replicated very efficiently in IFN-deficient CPT-Tert cells, but BTV8 H reached titers approximately 100-fold higher than its parental virus (Fig. 1A) . The data obtained so far indicate that BTV8 H had accumulated mutations that affected virus replication in IFN-competent cells and resulted in attenuation in vivo both in IFNAR Ϫ/Ϫ mice and in sheep.
cord-299549-bjqwwzam	2015	When the viral infection proceeds to the terminal stage, the key factor would be applying a non-specific immune modulation approach to suppress the cytokine storm that causes multiple organ failure, in an attempt to open a time window for the host''s immune system to recover. In most patients, Ebola viral burden elevates by time and triggers an extremely strong immune attack-a phenomenon called ''cytokine storm'' (Sullivan et al., 2003) , during which monocytes and/or macrophages produce a massive amount of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukins (ILs), and The virus burden, inflammatory response, and specific antibodies are the main contributors to different outcomes: mortality, survival, or symptomless infection (Fig. 2) , suggesting that the appropriate intervention strategy in each stage would accordingly be able to control the Ebola virus. Nonetheless, this phenomenon does give clues to the treatment against Ebola virus disease (EVD)-early activated innate immune responses may prevent the viral infection.
cord-299733-4mpz5l9e	2014	The mechanism of this differential response is consistent with a relative down-regulation of the NF-κB inflammatory cytokine induction pathway in the cynomolgus monkey and humans, but not observed systemically in rat. Primary protein sequences for the human (GenBank U88879); monkey species, including Macaca mulatta (Gen-Bank BAG55034.1 and AY864735), Macaca fasicularis ajp.amjpathol.org -The American Journal of Pathology (GenBank BAG55033.1), Papio anubis (XP_003899477), Callithrix jacchus (JAB01765.1), and Saimiri boliviensis (XP_003899477); and rodents, including the house mouse (GenBank AF355152/Mus musculus) and rat (GenBank AB116229/Rattus norvegicus), dog (GenBank XP_ 005630024/Canis lupus familiaris), and rabbit (GenBank ABB76310/Oryctolagus cuniculus) were aligned using Crystal W software version 10.1.2 provided by DNAStar (Madison, WI). The unexpected differential toxicities observed between the rat and a nonhuman primate prompted an examination of inflammatory cytokines (g-IFN, TNF-a, and IL-12p70) associated with infusion of a TLR3 agonist, rintatolimod.
cord-299754-tgexahwd	2017	Downstream of the initial pattern recognition, TRIMs also influence the recruitment and interaction of adaptor molecules (stimulator of IFN genes (STING), mitochondrial antiviral signaling protein (MAVS), TGF-β-activated kinase 1(TAK1)/MAP3K7-binding protein (TAB) 2, Myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapterinducing interferon-β (TRIF), NF-κB essential modulator (NEMO), nucleosome assembly protein (NAP-1), and tumor necrosis factor (TNF) receptor-associated factors (TRAF) family memberassociated NF-κB activator (TANK)) and enzymes (TRAF3, TRAF6, TAK1, inhibitor of NF-κB (IκB) kinase (IKK) α,β,ε, TANK binding kinase 1 (TBK1)) to signaling complexes in order to activate transcription factors. Downstream of the initial pattern recognition, TRIMs also influence the recruitment and interaction of adaptor molecules (stimulator of IFN genes (STING), mitochondrial antiviral signaling protein (MAVS), TGF-β-activated kinase 1(TAK1)/MAP3K7-binding protein (TAB) 2, Myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), NF-κB essential modulator (NEMO), nucleosome assembly protein (NAP-1), and tumor necrosis factor (TNF) receptor-associated factors (TRAF) family member-associated NF-κB activator (TANK)) and enzymes (TRAF3, TRAF6, TAK1, inhibitor of NF-κB (IκB) kinase (IKK) α,β,ε, TANK binding kinase 1 (TBK1)) to signaling complexes in order to activate transcription factors.
cord-299756-m0va36er	2009	As the BALB/c and the IFNAR-/129SvEv mice demonstrated very similar viral loads in their brains, we also compared their gene expression profiles upon infection with MHV in order to identify type I IFN-dependent transcriptional responses. CONCLUSION: Transcriptional profiling of mice infected with MHV demonstrated the induction of a robust IFN response, which correlated with the viral load. Furthermore, gene expression profiling of 129SvEv mice lacking the type I IFN receptor, which are not able to control the MHV infection [11] , allowed us to identify type I IFN-independent transcriptional responses. To study the role of type I IFN-independent and -dependent gene expression in the control of MHV infection in vivo in more detail, we next made use of the IFNAR-/-mice [30] . Transcriptional profiling of mice infected with MHV demonstrated the induction of a robust IFN response, which correlated with the viral load.
cord-299949-kmn53e2z	2016	For recovery from infection, the immune response in the central nervous system (CNS) must eliminate or control virus replication without destroying nonrenewable, essential cells. For recovery after virus infection of the central nervous system (CNS), the essential, nonrenewable nature of neurons requires a fine-tuned immune response that controls virus replication without damaging neuronal function. Detailed studies of immune responses to neurotropic viruses have included neuronal infections with rabies virus, flaviviruses, and alphaviruses, as well as infection of multiple cell types with natural mouse pathogens such as Theiler''s murine encephalomyelitis virus (TMEV), mouse hepatitis virus (MHV), and lymphocytic choriomeningitis virus (LCMV). Resident cells in the nervous system, including neurons, play an active role in the immune response (Schultz et al., 2014; O''Donnell et al., 2012; Chakraborty et al., 2010; Daffis et al., 2008a; Castorena et al., 2008; Daffis et al., 2007; Commonly used in mouse models of viral encephalitis.
cord-300319-9k8zseao	2004	To identify a model for the study of intestinal pathogenesis of severe acute respiratory syndrome (SARS) we tested the sensitivity of six human intestinal epithelial cell lines to infection with SARS coronavirus (SARS-CoV). In both cell lines, SARS-CoV infection deregulated expression of cellular genes which may be important for the intestinal pathogenesis of SARS. To investigate whether ACE2 is a functional receptor for SARS-CoV in intestinal epithelial cell cultures, the cells were pre-treated for 60 min at 37°C with goat antibody directed against the human ACE2 ectodomain (R&D Systems; Wiesbaden-Nordenstadt, Germany). SARS-CoV infection of Caco-2 cells up-regulated OAS2 and MXA but not PKR genes. The discrepancy between transcriptional activation of IFN-induced genes and the ability of SARS-CoV to replicate in Caco-2 cells could be explained by the existence of a specific viral mechanism for escaping IFNinduced anti-viral effects common to most viruses [28] . This justifies the use of intestinal cell lines as a model to study the direct effects of SARS-CoV infection on gene expression in permissive human cells.
cord-300648-ixiam7qr	2014	At 24 h post infection when the infected cells were examined by real-time RT-PCR assay, strikingly, DENV-2 infection was suppressed potently by the IFITM3-containing exosomes in a dose-dependent manner in parental HeLa cells (Fig. 4A ) or in HeLa cells with endogenous IFITM3 knocked down (Fig. 4C) , and the copy number of DENV-2 viral RNA was reduced in the culture supernatant ( Fig. 4B and D), indicating that the observed antiviral effect was mediated by the exosome-transferred IFITM3. To verify that the enhanced antiviral effects caused by IFITM3-exosome transfer was a result of IFITM3 action rather than a stimulated paracrine IFNs response, the concentration of human IFN-α/β in culture supernatant of HeLa cells or HeLa-siIFITM3 cells treated with IFITM3laden exosomes was measured with ELISA by using Sendai virus (SeV; 100 HAU ml −1 ) as a positive stimulus control.
cord-302340-pw2xqhwa	2011	Therefore, we have hypothesized that IFITM proteins inhibit susceptible virus families (Orthomyxoviridae, Flaviviridae, Rhabdoviridae, Filoviridae, and Coronaviridae) during the envelope-dependent early phase of the infection cycle, which extends from viral binding to cell surface receptors through the creation of the fusion pore between viral and host membranes [14, 19, 20] . B) MDCK cells stably overexpressing IFITM3 (MDCK-IFITM3) or empty vector control cells (MDCK-Vector) were exposed for 2 h to viral pseudoparticles containing a BLAM-Vpr and expressing either the HA and NA envelope proteins of Influenza A virus (WSN/33, H1N1pp) or the VSV-G envelope protein (VSV-Gpp), then loaded with CCF2. Our assays showed that incoming influenza A viruses were retained in the expanded acidic compartments of both the IFITM3 overexpressing cell lines as well as the IFN-c-treated MEFs, and that IFITM3 partially localized to these structures ( Fig. 2-4, S2-4, S6) .
cord-302401-oyhzn2kc	2019	
cord-302953-gr2kk9w4	2020	In Phase 1, during the first 7 to 8 days post infection (DPI), both infectious virus and viral RNA increase rapidly, followed by clearance of infectious virus that occurs primarily through cooperative effects of anti-SINV antibody and the cytokine interferon-gamma (IFN-γ) [6] [7] [8] [9] . Gbp2 ( Figure 2A ) and Irgm ( Figure 2B ), two genes associated with autophagy [25] , were highly expressed by SINV-infected dAP-7 cells treated with IFN-γ, as were Oasl2 ( Figure 2C ), a member of the 2''-5''oligoadenylate/RNaseL system [26] , and Rsad2 ( Figure 2D ), which encodes viperin, a protein that interferes with assembly and release of many viruses [27] . To determine the effects of IFN-γ signaling on immune cell subsets after SINV infection, cells isolated from the CLNs and brains of WT, Ifng −/− and Ifngr1 −/− mice were examined by flow cytometry. To determine the effects of IFN-γ signaling on immune cell subsets after SINV infection, cells isolated from the CLNs and brains of WT, Ifng −/− and Ifngr1 −/− mice were examined by flow cytometry.
cord-303189-ktl4jw8v	2015	Acting in both autocrine and paracrine manner, IFN interferes with viral replication by inducing hundreds of different IFN-stimulated genes with both direct anti-pathogenic as well as immunomodulatory activities, therefore functioning as a bridge between innate and adaptive immunity. In these cells, the HCV-induced miR-21 has been recently reported to be involved in evasion of IFN-I production and stimulation of HCV replication, upon suppression of MyD88 and IRAK1 expression, that is required for the TLR7-mediated sensing of the virus [100] . Amongst RNA viruses that, as HCV, can establish a persistent infection, HIV-1, a lentivirus from the Retroviridae family, represents a paradigm for its ability to prevent or circumvent the innate immune response mediated by IFN-I. Overall, viruses as HCV and HIV-1 have evolved nifty strategies to dampen the host innate response in cells where a productive infection may take place, while they induce infection-independent mechanisms in non-permissive cells to facilitate the viral life cycle and promote a chronic inflammation.
cord-303344-4aeu9n5v	2016	Lacking of USP18 leads to an increase signaling of IFN-I, IFN-III, TNF-α and high levels of conjugated ISG15 Interestingly, knockout mice generated on the FVB/N genetic background are more viable and do not exhibit the severe neurological symptoms that occur in mice generated on a C57BL/6 background, which develop brain injury because of necrosis of ependymal cells. 53 In addition to ISG15, USP18 also specifically inhibits K63-linked ubiquitination of NEMO, leading to the negative regulation of NF-κB activation induced by the TAK1-TAB complex. As expected, this upregulation inhibits IFN-I-induced genes in human microvascular endothelial cells; however, whether USP18 plays a role in controlling bacterial infection has not yet been fully clarified. Because DCs express more USP18 than do other types of cells, the lack of a response to the antiviral effect of IFN-I leads to augmented viral replication and a sufficient amount of autoantigen.
cord-303893-47lxq8pi	2020	Interferon beta-1a for COVID-19: critical importance of the administration route Juho Jalkanen 1 , Maija Hollmén 2 and Sirpa Jalkanen 2* Type I interferons, especially IFN-beta, have been appointed as potential leading therapeutics to tackle severe COVID-19 and are currently being evaluated in REMAP-CAP and the WHO''s Solidarity Trial. We wish to highlight the differences of these two treatment methods and also other crucial aspects of IFN-beta treatment for COVID-19 and acute respiratory distress syndrome (ARDS). Nonetheless, the purpose of i.v. administered IFN-beta for the treatment of COVID-19 and ARDS is to maximise bioavailability of the drug at the lung vasculature, as well as other vascular beds. There are a limited number of direct studies on the timing of immunomodulatory treatments such as IFN-beta, but given our basic understanding of human biology and viral defence, we suggest that IFN-beta should be given early to COVID-19 patients.
cord-304330-egvdvvtx	2020	William Damsky MD, PhD 1,* , Danielle Peterson MD 1 Brett King MD, PhD 1,* 4 5 has suggested that SARS-CoV-2 infection is sometimes characterized by a muted anti-40 viral Type I and III interferon (IFN) response, 6,7 which may explain progression to 41 severe clinical manifestations in some patients; a robust Type I IFN response was 42 associated with rapid viral clearance and bland disease course. Together, these data suggest that COVID toes may be a 46 marker of patients that are able to mount a robust anti-viral immune response to SARS-CoV-2 and prognosticate a milder course of COVID-19. 6,7 Therefore, we hypothesize that pernio-like lesions, which can 81 occur with elevated Type I IFN signaling, are the result of a robust anti-viral response in patients with COVID-19, and, therefore, are associated with a favorable disease course, 83 as observed in these patients. Pernio-like skin lesions associated 101 with COVID-19: a case series of 318 patients from 8 countries
cord-304457-8g36h1bz	2020	Conclusions: In a cohort of 63 hospitalized patients between 19 to 82 years-old with positive SARS-CoV-2, HeberFERON significantly negativized the virus on day 4 of treatment when comparing with IFN-alpha2b. The RT-PCR after treatment with IFNs on day 14 for hospital discharges was negative to SARS-CoV-2 in 100% and 91% of patients of HeberFERON and control cohorts, respectively. These results confirm the validity of early intervention with the treatment of IFNs in patients with COVID-19, whereas demonstrated in the trial, the combination of type I and type II IFNs impacts strongly in the reduction of the risk for a severe disease likely through the efficient implementation of a timely controlled inflammatory antiviral response against the SARS-CoV-2 infection. Evaluation of the Effect and Safety of HeberFERON vs Heberon Alpha in Patients Infected with Corona Virus SARS-CoV-2 (Study ESPERANZA/HOPE): TRIALS
cord-304553-gbwb7fqi	2008	Nonspecific, broad-spectrum immune responses can be induced by double-stranded (ds)RNAs such as poly (ICLC), or oligonucleotides (ODNs) containing unmethylated deocycytidyl-deoxyguanosinyl (CpG) motifs. Poly (ICLC), a dsRNA, and CpG ODNs, molecular mimics for TLR3 and TLR9, respectively, have been reported to non-specifically stimulate the innate immune system and to provide protection against various bacterial and viral pathogens, including influenza. Mice treated with two doses of poly (ICLC), 48 h apart, up to 12 d prior to viral challenge were completely protected from infection, whereas survival rates decreased to 80, 40 and 0%, when pre-treatment was given 14, 16 or 20 d prior to virus challenge, respectively [32] . CpG ODN treatment of splenocytes from senescence-accelerated SAM-P1 strain of mice increased IFN-γ and administration in vivo generated virus-specific cytotoxic T lymphocyte responses, NK cell activation, virus-specific Ig isotype switch from IgG1 to IgG2a, increased viral clearance and survival following influenza viral challenge. Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells
cord-304993-t4rua95e	2012	
cord-305093-og4k3fc7	2020	
cord-305263-fgwf6wy3	2012	IFN therapy therefore has the advantage over DAA treatments in that, in addition to stimulating genes that block viral replication in infected cells, IFNs activate other innate and adaptive immune responses to combat the virus. For example, polymorphisms in host genes encoding proteins associated with regulation of an IFN response such as interferon receptor a-chain (IFNAR1) [10] , the IFN-inducible myxovirus resistance GTPase protein, Mx [11] , the IFN-inducible 2 0 ,5 0 -oligoadenylate synthetase (OAS) [12] and the suppressor of cytokine signaling (SOCS) 3 associated with regulation of an IFN response [13] , are predictive markers linked with the rate of sustained virological response (SVR) to HCV infection following IFN-a treatment. Remarkably, distinct highly pathogenic respiratory viruses, namely influenza viruses and the SARS-CoV, encode nonstructural proteins in their genomes that function as virulence factors that specifically target the host innate IFN response, further emphasizing the importance of IFNs as broad-spectrum antivirals.
cord-305315-0qt7eth0	2015	title: Porcine epidemic diarrhea virus inhibits dsRNA-induced interferon-β production in porcine intestinal epithelial cells by blockade of the RIG-I-mediated pathway In this study, porcine small intestinal epithelial cells (IECs), the target cells of PEDV, were used as the infection model in vitro to identify the possible molecular mechanisms of PEDV-inhibition IFN-β production. CONCLUSION: Taken together, our data demonstrated for the first time that PEDV infection of its target cell line, IECs, inhibited dsRNA-mediated IFN-β production by blocking the activation of IPS-1 in RIG-I-mediated pathway. PEDV failed to induce IFN-β expression and inhibited poly (I:C)-mediated IFN-β production in IECs Type I IFNs (IFN-α/β) are critical to the host antiviral innate immune response. In summary, the findings of the present study suggested that PEDV-infection in IECs inhibits dsRNA-induced IFN-β induction by interfering with IRF-3 activity associated with RIG-I-mediated signaling pathway.
cord-305959-x061q8t7	2020	As the primary outcome, time to the clinical response was not significantly different between the IFN and the control groups (9.7 ± 5.8 versus 8.3 ± 4.9 days, respectively, P = 0.95). The vital signs at the time of hospital admission were not statistically different, except respiratory rate was significantly higher in the IFN group (22 versus 20, respectively, P ϭ 0.009). As a primary outcome, the time to clinical response was not significantly different between the IFN and control groups (9.7 Ϯ 5.8 versus 8.3 Ϯ 4.9 days, respectively, P ϭ 0.95), which is shown in the Kaplan-Meier plot (Fig. 2) . On day 0, there was no significant difference between the groups in terms of the components Interferon ␤-1a in Treatment of Severe COVID19 Antimicrobial Agents and Chemotherapy of this scale. The present study was the first randomized, open-label, controlled trial that assessed the efficacy and safety of IFN ␤-1a in the treatment of patients diagnosed with severe COVID-19.
cord-306424-gf0bglm0	2017	Thus, these data indicate that MAMs are critical locations for antiviral signaling and have an important role in expression of type I and III IFNs. Moreover, increasing evidence suggests that at least some +RNA viruses in fact occupy or hijack MAM-membranes during infection, as MAMs of HCV-infected cells were found to contain proteins involved in virus assembly and fully assembled virions [111] . At last, based on recent studies that demonstrated how IFN-g inducible GTPases are capable of disrupting PVs, we discussed the possibility of a general function of IFN-inducible GTPases in the targeting of viral ROs. In summary, upon infection, +RNA viruses hamper IFN and ISG induction at multiple levels to decelerate antiviral innate immune signaling. Antiviral innate immune response interferes with the formation of replication-associated membrane structures induced by a +RNA virus
cord-306533-lvm11o4r	2019	DUBs interact with some of the key molecules in the IFN signaling pathway, which include, but are not limited to, RIG-I, stimulator of interferon genes (STING), tumor necrosis factor receptor-associated factors (TRAFs), interferon regulatory factor are summarized in Table 1 . A study conducted using human kidney mesangial cells (MC) showed slightly different results: silencing CYLD in MC cells and stimulating them with poly IC increased the toll-like receptor 3 (TLR3)-induced activation of RIG-I and MDA5 [26] ; however, the level of mRNA of RIG-I and MDA5 actually decreased [26] . However, when USP18 -/-MEF cells with either WT USP18 or DUB activity-mutated USP18 were induced with HSV-1, HCMV or cytosolic DNA, Ifnb, Ifna4, Tnf, IL-6 or Cxcl1 genes increased in expression, indicating that the deubiquitinating activity of USP18 is not responsible for this phenomenon [41] . In a study by Malakhova et al., USP18 inhibited IFN-induced gene activation by affecting JAK-STAT signaling pathway in 293 T cells [44] .
cord-307333-n6jc0jy3	2014	OBJECTIVES: The airway expression of type III interferons (IFNs) was evaluated in infants hospitalized for respiratory syncytial virus (RSV) or rhinovirus (HRV) bronchiolitis. KEYWORDS IFN lambda; IL-28; IL-29; RSV; HRV; MxA; ISG56; Viral load; Bronchiolitis Summary Objectives: The airway expression of type III interferons (IFNs) was evaluated in infants hospitalized for respiratory syncytial virus (RSV) or rhinovirus (HRV) bronchiolitis. Therefore, we evaluated whether there was a difference in the gene expression of IFN lambda 1e3 subtypes between infants with a clinical diagnosis of RSV associated acute bronchiolitis and those with HRV infection. Results demonstrated that in cells collected from nasopharyngeal washings of RSV positive infants there are higher mRNA levels of type III IFNs compared to those observed in infants with Figure 1 Gene expression of IFN lambda 1e3 during RSV or HRV bronchiolitis.
cord-307598-p54p7enk	2013	Similar to TLRs, RIG-I and MDA5 induce type I IFN and chemokines (but no IL12) upon activation by viral but also bacterial RNA. Since type I IFN induction by this RNA required RNase L, the authors concluded that RNase L recognizes and processes viral mRNA into a MDA5 activating structure. Before 5 triphosphate was identified as the crucial RNA modification to induce RIG-I activation, Marques and colleagues observed that synthetic blunt ended dsRNA oligonucleotides can stimulate RIG-I ( Fig. 3 ) (Marques et al. (2010b) confirmed the requirement of a base paired 5 -ppp end of dsRNA for RIG-I activation and suggested that some arenaviruses and bunyaviruses use a prime and realign mechanism for genome synthesis, leading to 5 overhangs in order to evade RIG-I recognition (Marq et al. pneumophilae did not induce type I IFN in HEK293 cells, thus excluding RIG-I-mediated recognition of RNA polymerase-III transcripts in the host cell, as previously suggested (Chiu et al.
cord-307813-elom30nx	2018	Besides controlling virus replication, potential targets for drug development include controlling virus-induced host immune responses such as the recently suggested involvement of innate lymphoid cells and NADPH oxidases in influenza virus pathogenesis and immune cell metabolism. Besides controlling virus replication, potential targets for drug development include controlling virus-induced host immune responses such as the recently suggested involvement of innate lymphoid cells and NADPH oxidases in influenza virus pathogenesis and immune cell metabolism. A recent study using RNAi also demonstrated that cholesterol homeostasis can be regulated via acid phosphatase 2 (ACP2)-mediated Niemann-Pick C2 activity and impaired the membrane fusion of IAV and influenza B virus (IBV) (52) , further suggesting the importance of controlling cholesterol homeostasis in the release of viral genome to cytoplasm. Furthermore, FPR2 antagonists have been described to possess antiviral activity against not only IAV but also IBV infection (111) , promoting the idea that antagonizing FPR2 to suppress Raf/MEK/ERK signaling cascade could potentially be a novel approach for the treatment of a broad spectrum of influenza viruses.
cord-307914-lgprrwee	2020	Indeed, the functionalization of CRISPR/Cas systems as a tool for genomic editing have revealed important differences in human and murine NA sensing, including distinct cell subset expression patterns of NA-sensing Toll-Like Receptors (TLRs) or species differences in the structural requirements for the detection of cyclic dinucleotide cGAMP by STING. As a long dsRNA with a 5 0 diphosphate terminus, polyI:C is known to activate the sensing receptors TLR3, MDA5, and RIG-I (Alexopoulou et al., 2001; Gitlin et al., 2006; Kato et al., 2008; Yoneyama et al., 2005) , accessory proteins such including LGP2 and members of the DDX and DHX families (reviewed in Oshiumi et al., 2016) as well as the restriction factors PKR and the OAS family (Farrell et al., 1978; Hovanessian et al., 1977; Zilberstein et al., 1978) .
cord-308142-3x3n6cpt	2006	
cord-308298-5ntdb8yf	2013	Functional analyses revealed that splenic NKp46(high) NK cells produced much higher levels of Interferon-γ and Tumor Necrosis Factor-α upon stimulation with cytokines or phorbol-12-myristate-13-acetate/Ionomycin compared to the other two subsets. Splenic NKp46 high NK cells showed a significantly reduced level of CD8α expression compared to the other splenic NK-cell subsets in all animals analysed Sequences of primers (5''-3'') for target genes as well as primer positions on (+) strand, length of specific product in base pairs (bp) and product melting temperature in°C are indicated. Splenic NKp46 high NK cells showed an overall higher expression of this receptor compared to NKp46and NKp46 + NK-cell subsets from both spleen and blood. Splenic NKp46 high NK cells showed highly elevated expression of this activating receptor compared to the other two NKp46-defined subsets in spleen as well as in blood in all animals analysed, which could be demonstrated on protein as well as on mRNA level.
cord-308932-pp8etmwq	2012	Efforts to understand the immune systems of bats have been greatly facilitated in recent years by the availability of partial genome sequences from two species of bats, a megabat, Pteropus vampyrus, and a microbat, Myotis lucifugus, allowing the rapid identification of immune genes. Efforts to understand the immune systems of bats have been greatly facilitated in recent years by the availability of partial genome sequences from two species of bats, a megabat, Pteropus vampyrus, and a microbat, Myotis lucifugus, allowing the rapid identification of immune genes. Consistent with the results obtained from bats immunized with /X174 or SRBC antigens, vaccination and experimental viral infections have provided evidence for quantitative and qualitative differences in antibody responses in bats compared with other mammals. It is evident they have similar antibody and T-cell receptor genes, cytokines and chemokines, transcription factors, cluster of differentiation (CD) markers and activation pathways found in the immune responses of other mammalian species.
cord-309381-cb80ntxs	2019	IAV RNAs are mainly recognized by the endosomal, membrane-associated PRR Toll-like receptors (TLRs) 3 (double-stranded RNAs, dsRNAs) or 7/8 (ssRNAs), respectively [50, 51] , by the cytoplasmic PRR retinoic acid-inducible gene I (RIG-I), which detects dsRNA and 5 -triphosphates of the negative ssRNA viral genome [50, 52] , generated during replication of multiple viruses, by the NOD-like receptor family member NOD-, LRR-and pyrin domain-containing 3 (NLRP3), which recognizes various stimuli (see below) [53] and by the absent in melanoma 2 (AIM2) protein, recognizing not well-characterized influenza stimuli [54] . Another important SNP (rs34481144) associated with risk of severe influenza in humans from the United States (US) infected with seasonal IAVs is located in the 5 -UTR of the IFITM3 gene [123, 124] .
cord-309428-qkjjxr6p	2015	MicroRNAs (miRNAs) play important roles in viral infections, especially by modulating the expression of cellular factors essential to viral replication or the host innate immune response to infection. To identify host miRNAs important to controlling porcine reproductive and respiratory syndrome virus (PRRSV) infection, we screened 15 miRNAs that were previously implicated in innate immunity or antiviral functions. Luciferase reporters showed that miR-26a does not target the PRRSV genome directly but instead affects the expression of type I interferon and the IFN-stimulated genes MX1 and ISG15 during PRRSV infection. We found that miR-26a does not target the PRRSV genome directly, but rather affects the expression of type I interferon and the IFN-stimulated genes MX1 and ISG15 during PRRSV infection. Indirect immunofluorescence assays (IFA) were performed as described previously (Tian et al., 2011) for the detection of nucleocapsid (N) protein in PRRSV vJX143 infected MARC-145 cells or PAMs pre-transfected with miR-26 family or mutant mimics.
cord-309619-glb2y82u	2020	Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1–7)/Mas1R axis. SARS-CoV induces the signal transducer and activator of transcription 1 TACE TNF-a converting enzyme TBK1 TANK-binding kinase 1 TLR toll-like receptor TMPRSS2 type II transmembrane serine protease TNF-a tumor necrosis alpha TRAF3 TNF receptor-associated factor 3 XCR1 XCL1 (Chemokine [C motif] ligand 1) and XCL3 (Chemokine [C motif] ligand 3) receptor production of double-membrane vesicles that lack PRRs and can then replicate in these vesicles [18] . COVID-19 patients have high serum levels of inflammatory cytokines, including interleukin (IL)-2, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage SARS-CoV-2 infects primarily type II pneumocytes through binding to the ACE2 receptor. ACE2 = Angiotensin-converting enzyme 2; SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2; Ang II = Angiotensin II; ROS = Reactive oxygen species; AT1R = Angiotensin 1 receptor; ADAM17 = A disintegrin and metalloproteinase domain 17; TNF-a = Tumor necrosis factor alpha; TMPRSS2 = transmembrane protease serine 2.
cord-310252-0cdqhrcw	2008	Ag, antigen; APC, antigen presenting cells; APM, antigen-processing machinery; BH, bleomycin hydrolase; bp, base pairs; CIITA, class II transactivator protein; CLIP, class II invariant chain peptide; CTL, cytotoxic T lymphocyte; DC, dendritic cell; ER, endoplasmic reticulum; GAS, gammainterferon-activated site; IFN, interferon; IFN-R1, interferon-receptor-1; IL, interleukin; IRF, interferon regulatory factor; ISG, interferon-stimulated genes; ISGF3, IFN-stimulated gene factor 3; ISRE, interferon-stimulated response element; JAK, janus kinase; LPS, lipopolysaccharide; MAPK, mitogenactivated protein kinase; MCA, methylcholanthrene; MHC, major histocompatibility complex; NF, nuclear factor; NK, natural killer; PKC, protein kinase C; RCC, renal cell carcinoma; SCLC, small-cell lung carcinoma; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; TA, tumor antigen; TAP, transporter associated with antigen processing; TCR, T cell receptor; TFBS, transcription factor-binding sites; TNF, tumor necrosis factor; tpn, tapasin; TPPII, tripeptidyl peptidase II; TSA, trichostatin A; TYK, tyrosine kinase; UIRR, upstream interferon response region; USF1, upstream stimulatory factor 1; wt, wild type.
cord-310396-jitao9k0	2009	
cord-310444-02dsqbeg	2012	Conclusion Our data suggest that the failure of STAT1-deficient mice to efficiently control initial SARS-CoV replication in the lung is due to impaired type I and type III IFN signaling, whereas the failure to control subsequent systemic viral spread is due to unrelated defects in STAT1-deficient mice. The type III interferons are especially important in pulmonary infection, produced in response to viral infection and bacterial PAMPs. IFN-k is activated by and induces NF-jB signaling and promotes expression of Th1 cytokines. Consistent with the expected participation of IFN-k in NF-jB signaling, we measured decreased expression of KC, TNF and GM-CSF and increased IL-10 in the IL-28RÀ/ -BAL (P < 0.05), although there were no significant differences in the populations of immune cells (neutrophils, DC, macrophages) recruited to the airways of the wild type or IL-28RÀ/À mice. Ligation of immunoreceptor tyrosine-based activation motif (ITAM)associated receptors in macrophages can initiate potent induction of negative regulators, including anti-inflammatory cytokine IL-10, signaling inhibitors SOCS3, ABIN3, A20 and transcriptional repressor Hes1 [1] .
cord-310469-v4p01rze	2007	Thus, in an effort to characterize antiviral agents that could attenuate infections caused by OROV, CARV, GMAV, GROV and TCMV, we tested the in vitro and in vivo actions of IFN-␣ on these viruses. However, treatment of CARV-, GMAV-or TCMV-infected mice with IFN-␣A did not result in an increase in survival or prolongation of the mean time to death and did not prevent virus replication in the brain of animals (Table 2 and Fig. 3, respectively) . Treatment with IFN-␣A initiated 24 h after mice infection by GROV was unable to inhibit either the death of animals or the viral replication in the brain (Table 3 and Fig. 5 , respectively). In vitro and in vivo results showed that IFN-␣ was able to prevent viral replication in a limited manner, exerting antiviral effect only when administrated early and in high doses, suggesting that OROV, CARV, GMAV, GROV and TCMV present some escape mechanism from antiviral actions of the IFN-␣.
cord-310861-9kb0b6rq	2017	In this study, we report an isothermal and rapid one-step RNA amplification/detection (iROAD) assay to simultaneously amplify and detect the viral RNA in a label-free and real-time manner. Furthermore, we demonstrated the clinical utility of the iROAD assay by detecting respiratory viral RNAs extracted from the 63 nasopharyngeal samples with either IFN-A/B or HCoV-OC43/229E or RSV-A/B. Subsequently, the iROAD assay detected the respiratory viral targets from the clinical sample by measuring the resonance wavelength shift within 15-20 min (Fig. 1) . In case of the iROAD assay with label-free and real-time capabilities, the wavelength shift was sequentially increased based on the concentrations (2.5×10 1 to 10 5 copies/reaction) of IFN-B within 20 min, as compared to the negative control. In the case of the real-time RT-PCR assay, the fluorescent SYBR Green signal was observed in RNA samples diluted up to 2.5×10 2 copies/reaction and showed good linearity (R 2 =0.9795) for different concentrations of the target (Fig. 3C ).
cord-310942-191m0e65	2012	
cord-311718-z64g8fce	2020	Type I Interferon (IFN) signaling plays an important role in the immune defense system against virus infection and in the innate immune response, thus IFNs are widely used as anti-viral agents and treatment for immune disorder or cancer. We designed and synthesized a series of arylpiperazine derivatives as interferon inducers  We tested different linker system and carbonyl moiety resulted in increase of potency  5i exhibited the activity of interferon inducer with EC 50 of 13.1 μM and no cytotoxicity  5i initiated immune responses by mediating type I IFN signaling Based on these important characteristics of the ARP skeleton, we designed and synthesized a series of 2,3-dichloro ARP derivatives by further N-modification on piperazine part with different linker moiety such as thiourea, urea, and carbonyl functional group in order to assess structure-activity relationship (SAR; Figure 1b All the synthesized compounds were evaluated using ISRE reporter assay on THP-1 human monocyte cells for monitoring immune response.
cord-311823-85wj08gr	2008	In this section, we review recent studies in which genomic approaches have been used to provide new information on how viruses trigger and regulate innate immune pathways, and to evaluate the use of type I IFN-based therapy as a means to enhance the innate immune response to HCV. In RIg-I-deficient cells, influenza virus fails to elicit the expression of IFNβ and of many ISgs, including key antiviral mediators such as IRF3, STAT1 (signal transducer and activator of transcription 1), IFIT1 (IFN-induced protein with tetratricopeptide repeats 1; also known as ISg56) and ISg54 (also known as IFIT2). Although these studies have provided considerable information regarding the genes activated downstream of TlR activation, it will be advantageous to extend genomic analyses in the context of viral infection using cells lacking the expression of specific TlRs. The ability of a virus to establish an infection depends, at least to some extent, on its ability to block the host innate immune response or to modulate the activity of antiviral effector proteins.
cord-312001-8p7scli8	2019	Consequently, animal cells have evolved devoted pathways which (1) sense and recognize pathogen-associated molecular patterns (PAMPs) and, more particularly, virus-associated molecular signatures; (2) initiate signaling cascades stemming from the site of detection, translocating the information to the nucleus; and (3) induce a transcriptional program that confers an antiviral state to the host ( Figure 1 ). While the cytosolic recognition of viral RNA is almost exclusively mediated by RLRs, several proteins have been proposed to play a role in DNA sensing and triggering innate immune responses, such as the DNA-dependent activator of IFN-regulatory factors (DAI), DDX41, RNA polymerase III, IFI16 and DNA-PK [62] [63] [64] [65] [66] [67] . Although the pathway leading to the transcriptional activation of Vago is still poorly understood in insects, these studies established that DExD/H-box helicase containing proteins, like Dicer and RLRs, may represent an evolutionarily conserved set of viral nucleic acid sensors that direct antiviral responses in animals [159] .
cord-312075-asbt0mcj	2016	Human T-cell lymphotropic virus type I (HTLV-1) protein Tax disrupts innate immune signaling in multiple ways: it binds to the RIP homotypic interaction motif (RHIM) domains of RIP-1 and disrupts the interaction between RIP-1 and RIG-I or MDA-5 and the activation of the type I IFN promoter. Upon stimulation, TBK1 and IKKε are recruited by adaptor proteins to signaling complexes to be activated by phosphorylation on Ser172 and both have been shown to be subjected to K63-linked polyubiquitination [reviewed in Ref. Interestingly, when a recent study tested how the rabies virus P protein of street strains behaves compared to laboratory-adapted strains with regard to the induction of type I IFN, they found that both street strains and laboratory strains inhibit TBK1-mediated signaling, but only the P protein of street strains also interacts with and inhibits IKKε-inducible IRF3dependent IFNβ expression (88) (Figure 1) . Middle east respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3
cord-312386-88uwlmjx	2015	Signal transducer and activators of transcription-3 (STAT3) regulates diverse biological functions including cell growth, differentiation, and apoptosis. Signal transducers and activators of transcription (STATs) are a family of transcription factors that play crucial roles in regulating a number of diverse biological functions including cell proliferation, differentiation, apoptosis, inflammatory response, immunity, and angiogenesis [1] . The seemingly contradictory roles of STAT3 in viral infections raise a number of interesting questions: "what factors determine the switch between pro-and anti-inflammatory functions of STAT3?," "how are viruses able to exploit STAT3 signalling for their gene replication?," and "does STAT3 either negatively or positively regulate type 1 IFN response depending on the virus type involved?" Further in depth studies to dissect the role of STAT3 in viral infections could provide valuable insights into viral pathogenesis and development of novel antiviral therapies. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins
cord-312438-zr9zx7pv	2020	
cord-312955-gs65c3fy	2020	Although SARS-CoV-2 inhibits the production of IFNβ and thus obstructs the innate immune response to this virus, it is sensitive to the antiviral activity of externally administrated IFN-Is. In this review I discuss the diverse modes of biological actions of IFN-Is and how these are related to biophysical parameters of IFN-I–receptor interaction and cell-type specificity in light of the large variety of binding affinities of the different IFN-I subtypes towards the common interferon receptor. Thereby, it inhibits the nuclear transport of phosphorylated STAT1, rendering cells refractory to IFN-Is. Another example of viral mechanisms that evolved to eliminate IFN-I functions in inducing innate immunity is given by the SARS corona virus, where both the production of IFNb and the IFN-I induced signaling are attenuated. This gene was found to preferentially cleave the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), FIGURE 4 | SARS-CoV-2 has multiple effects on the immune system, including inhibition of IFNb production, which results in ISGs not to be produced, CD4+ and CD8+ exhaustion and increased levels of pro-inflammatory proteins (TNFa, IL6, NF-kB).
cord-313445-4v7pjqt2	2020	
cord-313684-61hkogdh	2020	Coronavirus disease 2019 (COVID-19), an acute onset pneumonia caused by a novel Betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in the Wuhan City of China in December 2019 and evolved into a global pandemic. These include antivirals (remdesivir, lopinavir/ritonavir, umifenovir, and favipiravir), interferon, antimalarials (chloroquine/hydroxychloroquine), antiparasitic drugs (ivermectin and nitazoxanide), biologics (monoclonal antibodies and interleukin receptor antagonist), cellular therapies (mesenchymal stem cells and natural killer cells), convalescent plasma, and cytokine adsorber. Though several observational studies have claimed many of these agents to be effective based on their in vitro activities and extrapolated evidence from SARS and Middle East respiratory syndrome (MERS) epidemics, the currently available data remains inconclusive because of ill-defined patient selection criteria, small sample size, lack of concurrent controls, and use of intermediary outcomes instead of patient-relevant outcomes.
cord-313957-hviv5zar	2020	
cord-314019-8n0jafsk	2014	
cord-314333-hkyiy1gm	2008	title: Mouse-Passaged Severe Acute Respiratory Syndrome-Associated Coronavirus Leads to Lethal Pulmonary Edema and Diffuse Alveolar Damage in Adult but Not Young Mice Adult mice showed early and acute excessive proinflammatory responses (ie, cytokine storm) in the lungs after SARS-CoV infection, which led to severe pulmonary edema and diffuse alveolar damage. Because advanced age is associated with higher mortality in human SARS patients and SARS-CoV replicates better in aged mice, 6 -10,29 we experimentally infected 6-month-old (adult) female BALB/c mice with F-musX-VeroE6 or the Frankfurt 1 isolate. With regard to the cytokine responses of the mice, the lung homogenates of adult mice on day 1 after inoculation had significantly higher levels of monocyterelated chemokines [ie, MCP-1, macrophage inflammatory protein 1 (MIP-1), and IFN-␥-inducible protein 10 (IP-10)] than those from young mice ( Figure 5 ).
cord-314505-7qh8dsew	2019	The induction of the IFN response following viral infections fundamentally changes the bone marrow microenvironment ( Figure 1B) , leading to the enhanced differentiation of myeloid cells [24] and emigration of neutrophils and monocytes to the site of infection, which is facilitated by chemokine gradients interacting with their cognate receptors ( Figure 1A ) [25] . TLR stimulation after phagocytosis activates the NF-κB signaling cascade, resulting in the release of inflammatory cytokines such as TNF-α, IL-1, and IL-6 from monocytes [4] to control virus infections by direct antiviral mechanisms and the recruitment of other leukocytes. Taken together, these findings suggest that type I IFN signaling drives a balance of pro-and anti-inflammatory effects on the functions of monocytes and neutrophils in response to viral infections; providing protective immunity while simultaneously limiting immunopathology. Importantly, viruses and virus-mediated tissue damage stimulate both neutrophils and monocytes, triggering a cascade of cytokine/chemokine-mediated innate immune responses.
cord-315072-b28yikvj	2016	title: Chicken interferome: avian interferon-stimulated genes identified by microarray and RNA-seq of primary chick embryo fibroblasts treated with a chicken type I interferon (IFN-α) To generate a chicken ISG database we have compared data from three transcriptomic technology platforms: (i) the classical 3′-biased GeneChip Chicken Genome Array (32K; Affymetrix, High Wycombe, UK), (ii) the Chicken Gene 1.0 Sense Target (ST) whole transcriptome Array (Affymetrix) and (iii) Illumina (Little Chesterford, UK) RNA-seq. One of the most highly-expressed contigs was one which, when analysed by BLAST, proved to represent a homologue of STAT2, which is missing from the current ENSEMBL annotated reference chicken genome In (B) PYURF shows 24-fold suppression by IFN but the sequence surrounding PYURF shows 87-fold induction from the right-hand end of the unannotated, antisense LOC422513 and considerably higher upregulation from the left-hand end (due to its lower uninduced levels), consistent with these representing homologues of IFN-inducible human genes HERC6 and HERC5. Technologies identifying significant IRGs are listed as "1" RNA-seq (using Kal''s Z test); "2" Affymetrix 32K GeneChip Chicken Genome Array and "3" Chicken Gene 1.0 ST Array'' .
cord-315328-8g40ukml	2020	In this report, we demonstrate that IFN-β-1a was highly effective in inhibiting in vitro SARS-CoV-2 replication at clinically achievable concentration when administered after virus infection. In this report, we demonstrate that IFN-β-1a was highly effective in inhibiting in vitro SARS-CoV-2 replication at clinically achievable concentration when administered after virus infection. In the current study, we assessed its anti-SARS-CoV-2 activity in vitro to give a preclinical background to clinical trials evaluating the possible therapeutic role of IFN-β-1a in patients with coronavirus disease 2019 (COVID-19). Vero E6 cells were treated with concentrations ranging from 5000 to 0.01 IU/mL of IFN-β-1a 1 hour after inoculation with SARS-CoV-2 and monitored for cytopathic effect and real-time-PCR quantitative evaluation at 48, 72, and 96 hours after infection. Our in vitro observations shed light for the first time on that antiviral activity of IFN-β-1a against SARS-CoV-2 when administered after the infection of cells, highlighting its possible efficacy in an early therapeutic setting.
cord-315483-l6dm82pp	2018	To confirm the sequence of the cDNA and to identify the genomic structure of the identified IFIT gene, the transcript was amplified from RNA extracted from NDV-infected CEFs. Complete sequence analysis of the gene revealed an open reading frame (ORF) of 1440 bps (479 amino acids excluding stop codon) with high sequence identity (48% and 67%) with the human and duck IFIT5 proteins, respectively ( Supplementary Fig. 1B) . The levels of chIFN-β gene induction was proportional to the NDV replication (Fig. 2D) , therefore, it can be inferred that the virus-induced expression of chicken IFIT5 is IFN-dependent and that chIFIT5 is an early-ISG with capacity to modulate initial steps of virus life cycle. To compare anti-viral effects of chIFIT5 (only IFIT gene identified in chickens so far) with its orthologous and homologous human proteins, huIFIT1, huIFIT2, huIFIT3 and huIFIT5 were expressed in chicken cells and antiviral affect was monitored (Fig. 5A ).
cord-315730-fzgxuak7	2020	Owing to their efficacy against viruses (mostly demonstrated in vitro) including influenza, HIV, coronavirus OC43, and SARS-CoV, a large number of clinical trials (>230) have been registered worldwide using chloroquine/hydroxychloroquine alone, or in combination with other drugs (e.g. azithromycin) for the treatment of COVID-19. At the time of writing, the RECOVERY trial (clinical trial identifier NCT04381936) which is the largest randomised control trial so far conducted for the treatment of COVID, has stopped recruiting to the hydroxychloroquine arm (1542 patients compared with 3132 on standard care) because of no beneficial effect either in terms of mortality or hospital stay (P. Assessment of QT Intervals in a Case Series of Patients With Coronavirus Disease 2019 (COVID-19) Infection Treated With Hydroxychloroquine Alone or in Combination With Azithromycin in an Intensive Care Unit Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial
cord-317333-unrd76bo	2011	Evaluation of gene expression patterns in PBMCs and lung necropsies of SARS-CoV-infected ferrets led us to the identification of 7 upregulated IRGs that also were upregulated in response to IFN-α2b injection. Since STAT1 was phosphorylated following SARS-CoV infection and IFN-α2b injection, we investigated select IRG expression by qRT-PCR following in vitro stimulation of ferret peripheral whole blood with IFN-α2b. These gene expression and STAT1 phosphorylation findings suggested that robust IFN responses were activated following SARS-CoV infection 2 days post-infection. The comparison of microarray results between the lung tissue of IFN-α2b and SARS-CoV ferrets at day 1 revealed commonalities in the expression patterns of most IRGs. STAT1, MX1, OAS1, OAS2, ISG15, IFI44, IFI44L and EIF2AK2 were among the overlapping genes (Fig. 3B ). Analysis of the IFN signaling canonical pathway showed the upregulation of STAT1, MX1, OAS1, OAS2, ISG15 and IFI44 in lung necropsies of IFN-α2b injected and SARS-CoV infected ferrets (Fig. 4) .
cord-317499-mxt7stat	2014	Table 1 shows the frequency of HRV infection in various adult respiratory diseases such as exacerbation of asthma (Nicholson et al., 1993; Atmar et al., 1998; Tan et al., 2003) , common cold (Makela et al., 1998; van Gageldonk-Lafeber et al., 2005) , exacerbation of COPD (Seemungal et al., 2001; Rohde et al., 2003; Tan et al., 2003; Beckham et al., 2005; Papi et al., 2006; Hutchinson et al., 2007; Ko et al., 2007; McManus et al., 2008; Kherad et al., 2010; Dimopoulos et al., 2012; Perotin et al., 2013) , community acquired pneumonia (Jennings et al., 2008; Johnstone et al., 2008; Johansson et al., 2010; Lieberman et al., 2010; Fry et al., 2011; Wootton et al., 2011; Luchsinger et al., 2013; Takahashi et al., 2013; Huijskens et al., 2014) , exacerbation of idiopathic pulmonary fibrosis (Wootton et al., 2011) , and asymptomatic infection (Fry et al., 2011) .
cord-317573-wp2wr3b5	2006	In this study, we found that peripheral blood mononuclear cells (PBMCs) from fully recovered SARS individuals rapidly produced IFN-γ and IL-2 following stimulation with a pool of 9 peptides overlapping the entire E protein sequence. To assess memory T cell response specific for E protein after SARS-CoV infection in humans, PBMCs from individuals who had fully recovered from SARS two years after infection were stimulated with a pool of 9 peptides spanning the entire amino acid sequence of the SARS-CoV E protein, or the cells were stimulated with anti-CD3 and anti-CD28 antibodies under the same culture conditions as positive controls. Similarly, the frequency of SARS-CoV E antigen-specific IFN-g-producing cells determined by IFN-g ELISPOT assay in PBMCs from 8 fully recovered SARS individuals was significantly higher than that of the cells from the normal donor controls in response to E peptides (Fig. 1B) .
cord-318070-8txogxek	2006	
cord-318339-j35w1vsw	2006	METHODS AND FINDINGS: In response to the WHO request we conducted a systematic review of the published literature on ribavirin, corticosteroids, lopinavir and ritonavir (LPV/r), type I interferon (IFN), intravenous immunoglobulin (IVIG), and SARS convalescent plasma from both in vitro studies and in SARS patients. In response to the WHO request we conducted a systematic review of the published literature on ribavirin, corticosteroids, lopinavir and ritonavir (LPV/r), type I interferon (IFN), intravenous immunoglobulin (IVIG), and SARS convalescent plasma from both in vitro studies and in SARS patients. This paper reports on this systematic review designed to summarise available evidence on the effects of ribavirin, lopinavir and ritonavir (LPV/r), corticosteroids, type I IFN, intravenous immunoglobulin (IVIG), or convalescent plasma in relation to (1) SARS-CoV replication inhibition in vitro; (2) mortality or morbidity in SARS patients; and (3) effects on ARDS in adult patients.
cord-318364-5bmdzgla	2020	In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response. In support of the above observations, a retrospective study of 41 patients with COVID-19 2 showed that most SARS-CoV-2 infected patients present clinically with mild symptoms, while a minority of patients progressively declined from the infection and eventually died of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MOD). Severe pneumonia caused by pathogenic human coronaviruses (HCoV) are often associated with induced hypercytokinemia, also termed cytokine storm, in immunocompetent individuals; uncontrolled overproduction of inflammatory cytokines contributes to acute lung injury and acute respiratory distress syndrome (ARDS).
cord-319248-ynoxec7k	2020	
cord-319501-a2x1hvkk	2016	Particularly, the host pathogen recognition receptors and the signal transduction pathways to mount an effective antiviral response against SARS and MERS coronavirus infection are discussed. This suggests SARS-CoV N may interfere with RNA recognition by host immune sensors such as RIG-I and MDA5 thus achieving suppressive role in IFN production. Our group demonstrated that MERS-CoV ORF4a interacts with PACT, a cellular dsRNA-binding protein that optimally activates RIG-Iand MDA5-induced type I IFN production, in an RNAdependent manner (Siu et al., 2014c) . Infection with SARS-CoV and MERS-CoV has been accompanied with suppression of innate immune response, most notably with the suppression of type I IFN production and signaling pathways. Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells Middle East respiratory syndrome coronavirus 4a protein is a double-stranded RNA-binding protein that suppresses pact-induced activation of RIG-I and MDA5 in the innate antiviral response
cord-319761-bu5pzbnv	2005	
cord-319779-n5w1f0rr	2004	North American porcine reproductive and respiratory syndrome virus (PRRSV) field isolates were studied with regard to IFN-α sensitivity and induction in order to understand the role of type I IFN in PRRSV pathogenesis. PRRSV isolates were differentially sensitive to porcine recombinant IFN-α (rIFN-α) and varied in their ability to induce IFN-α in porcine alveolar macrophages (PAM) cultures as measured by a porcine IFN-α specific ELISA on cell culture supernatants. In this study, North American field isolates of PRRSV were evaluated with respect to induction, sensitivity and suppression of an in vitro type I IFN response. UV-inactivated PRRSV stocks were tested to determine whether virus binding to the cells is responsible for enhanced IFN-a production by polyI:C in cells infected with isolate 3 (Fig. 6) . In this study, North American PRRSV field isolates were evaluated with respect to induction, sensitivity and suppression of an in vitro IFN response in PAM cultures. Immune responses in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV)
cord-320338-jv76j6wx	2017	In this study, we found that the addition of exogenous cytidine, uridine and uridine mono-phosphate (UMP) effectively reversed the antiviral activity of gemcitabine in enterovirus-infected as well as enteroviral replicon-harboring cells, demonstrating gemcitabine''s targeting of the salvage pathway. At first, in order to test if the anti-enteroviral activity of gemcitabine is related with the inhibition of pyrimidine biosynthesis, HeLa cells were infected with CVB3 and simultaneously treated with excessive 4 nucleosides (adenosine, guanosine, uridine and cytidine) in the presence of various doses of gemcitabine for 8 hours. HeLa cells were treated with increasing doses of gemcitabine or IFN-α for 24 hours and then total RNAs were prepared for quantitative real-time PCRs. As a result, gemcitabine strongly induced two genes (IFIT1 and DDX58) up to and UMP) (100 μM) of pyrimidine biosynthetic pathway were treated as described in Figure 1A (A) and in Figure 1B (B) .
cord-320663-xypg6evo	2020	A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. Natural Killer (NK) cells are a key component of the innate immune system and are critical in the response to many viral infections in humans and animal models (1) (2) (3) . Altogether these studies show that during acute CoV infection, inflammatory monocyte-macrophages and neutrophils accumulate in the lungs and produce cytokines and chemokines that induce the activation and migration of lymphocytes, including NK cells, to the lungs, where they could be one of the main producers of IFN-γ (148). Studies have reported that patients infected with SARS-CoV-2 have lower levels of circulating NK cells and these express a greater level of inhibitory receptors (e.g., NKG2A) while producing less IFN-γ (127, 129, 130) .
cord-321050-yabt72jf	2020	Increasing evidence supports the notion that mortality during infections with SARS-CoV-2, which causes coronavirus disease of 2019 , is driven by the exacerbated immune response to the virus, leading to a cascade of events involving a cytokine storm and acute respiratory distress syndrome (ARDS), often accompanied by myocardial damage and multiple organ failure (5, 6) . Overall, these results have potential far-reaching significance for the treatment of COVID-19, justifying a deeper study of JAK inhibitors as a therapeutic strategy to attenuate the cytokine storm and downstream organ failure in this condition, while also indicating that individuals with DS should be considered a high-risk population during the COVID-19 pandemic. This analysis revealed that Dp16 mice have increased liver pathology even before P(I:C) treatment, as demonstrated by significantly higher levels of cell injury, inflammation, and reactive changes relative to their WT littermates (Figure 4B,C) .
cord-321947-qek9jy2c	2020	In VZV-primed mice, we assessed whether this ssRNA adjuvant induces humoral-and cell-mediated immunity in the VZV gE subunit vaccine. However, we used guinea pigs to evaluate the ability of the ssRNA adjuvant to enhance neutralizing antibody production and cell-mediated immune response in VZV LAV. Based on all results, we showed the potential of ssRNA adjuvants to compensate for the limitations of protein-based vaccines with respect to low T-cell activity and short-term responses, as well as to increase the neutralizing antibody in LAV for preventing VZV-induced disease. 41 Here, the ssRNA adjuvant-induced humoral and balanced Th1/Th2 immune responses even though its antibody and cytokine induction levels in the VZV gE protein subunit vaccine were lower than those for AddaVax. Nevertheless, the mode of action of AddaVax has not yet been elucidated. Moreover, the ssRNA derived from CrPV IGR IRES encoding the gE gene, which could express gE in transfected cells, can effectively function as a vaccine adjuvant in a protein-based subunit vaccine by activating humoral and cell-mediated immune responses.
cord-321992-lk2ao6m8	2015	In the present study, we investigated the innate immune responses such as cytokine and NK cell activity as well as changes in frequencies of T cells to examine if differences coincide with the higher disease severity of suckling versus weaned pigs. The infected weaned pigs also had significantly higher NK cell frequencies in blood and ileum at PID 5 (P < 0.05) compared to infected suckling pigs ( Fig. 2A and B) . In infected suckling and weaned groups, peak IFN␣, IL-12 and TNF␣ levels coincided with onset of diarrhea and fecal PEDV RNA shedding and peak serum PEDV RNA titers (PIDs 1 and 3, respectively); and (4) Frequencies of CD3+CD4+ T cells were significantly higher in ileum of suckling pigs than in weaned pigs, whereas there was no difference in frequency of CD3+CD8+ T cells.
cord-322683-wkrj6n1d	2020	title: Cellular Poly(C) Binding Protein 2 Interacts with porcine epidemic diarrhea virus Papain-Like Protease 1 and Supports Viral Replication Taken together, these data demonstrated that PLP1 negatively regulated the production of type 1 interferon by interacting with PCBP2 and promoted PEDV replication. The PEDV N protein interacts with the TANK-binding kinase, blocking its association with interferon regulatory factor 3 (IRF3) and thus inhibiting IRF3 activation and type I IFN production (Ding et al., 2014; Hu et al., 2018) . PCBP2 expression is induced following viral infection and acts as a negative regulator of mitochondrial antiviral signaling protein (MAVS), triggering its degradation (You et al., 2009) . Although significant progress has been made in understanding PEDV evasion of innate immune responses, the mechanism of interaction between viral and host cell proteins remains unclear. In the present study, we demonstrated that PLP1 interacted with PCBP2 to inhibit IFN-β production and promote PEDV replication.
cord-323713-bc00vths	2019	RESULTS: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Stimulator of IFN genes (STING)-associated vasculopathy with onset in infancy (SAVI) is caused by gain of function mutations in TMEM173 [3] , which lead to a constitutive production of high levels of type I IFNs without infectious triggers [3] [4] [5] . Notably, the clinical responses did not correlate with decreased type I IFN signatures, which improved only transiently in P1 during concomitant treatment with high dose steroids and ruxolitinib (Fig. 2b) . P3 (follow-up of 12 months) after ten months on treatment on ruxolitinib presented clinical and radiological relapse of lung disease requiring glucocorticoid therapy (2 mg/kg/day of prednisone) with a prompt response (Fig. 2a) .
cord-323756-atnrw9ew	2013	When Janeway formulated the theory of pattern recognition in 1989, he proposed that host cells could sense microbial infection owing to receptors able to recognize invariant molecular structures defined as pathogen-associated molecular patterns (PAMPs). They share a similar organization with three distinct domains: (i) a C-terminal repressor domain (RD) embedded within the C-terminal domain (CTD); (ii) a central ATPase containing DExD/H-box helicase domain able to bind RNA; and (iii) a N-terminal tandem CARD domain that mediates downstream signaling, and which is present in RIG-I and MDA5 but absent in LGP2. DDX60 has also been shown to enhance the IFN-I response to RNA and DNA stimulation through formation of complexes with Frontiers in Immunology | Molecular Innate Immunity RIG-I, MDA5, and LGP2 but not with MAVS. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses
cord-324674-yd7idp90	2018	
cord-325624-6anybxnk	2009	The unique phenotype of infected RL(−/−) mice was rather manifested in earlier onset and increased severity of demyelination and axonal damage in brain stem and spinal cord without evidence for enhanced neuronal infection. RNase L specifically protected the brain stem from sustained infection and prevented spread of virus to microglia/macrophages located in spinal cord grey matter. The increased pathological changes in both brain stem and spinal cord thus correlated with the high mortality rates of RL 2/2 mice starting at day 9 p.i. The inability to directly link increased axonal damage with enhanced neuronal infection remains puzzling and supports dysregulation of oligodendrocyte function and/or neuroprotective functions of microglia as contributing factors to the severe pathological phenotype and clinical outcome. Numerous functions of RNase L, not directly associated with anti-viral activity, may contribute to the increased susceptibility of RL 2/2 mice to MHV-JHM infection.
cord-325825-0lyt8gfq	2013	Host factors (HFs) which positively or negatively regulate HSV-1 replication were identified by screening a druggable genome siRNA library (4 siRNAs per gene) targeting 7,237 human genes against a HSV-1 reporter virus expressing the enhanced green fluorescent protein (eGFP; HSV-1 strain C12) in the epithelial Hela cell line, due to their ease of transfection and susceptibility to HSV-1 infection [34] . Combined bioinformatic analyses of protein interaction and siRNA depletion screens found a significant functional enrichment for proteins involved in transcription, and identified multi-protein complexes enriched for pro-viral HFs which strongly inhibited HSV-1 upon depletion, including the RNA-polymerase II, eIF3 and Mediator complexes ( Figure 3a) . Furthermore, qPCR analysis found depletion of Med23 inhibited the induction of IFN-l expression following HSV-1 infection of A549 cells in comparison to cells transfected with the RSCF siRNA control ( Figure 4e ).
cord-325989-nf6ouaq3	2012	The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. Better characterization of pathogen-induced immune disorders and newly discovered regulators of innate immunity have now the potential to specifically withdraw prevailing subversion mechanisms and to transform antiviral treatments by introducing panviral therapeutics with less adverse effects than IFN therapies. In the near future, targeting specific regulators of PRR-mediated innate response to withdraw viral subversion mechanisms, and access to novel surrogate measurable effector markers, hold the promise of new panviral therapeutics that will minimize adverse effects associated with type I IFN therapy.
cord-326762-t89jtjmi	2011	title: Establishment of a stable CHO cell line with high level expression of recombinant porcine IFN-β Abstract A CHO cell clone (CHO-PoIFN-β) with stable porcine IFN-β expression under control of CMV promoter was selected under G418 pressure. The purpose of this study was to establish highly efficient and stable expression of recombinant porcine IFN-b in CHO-K1 cell line, and further characterize the biological activity of the product. In order to study the antiviral capacity of recombinant PoIFN-b against porcine viruses in vitro, PK15 cells were treated with 10-fold serially diluted PoIFN-b CHO (start from1.1 Â 10 6 IU/ml) for 24 h, and then infected with 1000 TCID 50 of TGEV (Fig. 4A-C) or PRV (Fig. 4F-H) . The CHO-PoIFN-b cell line established in this study expresses the recombinant PoIFN-b that has the same biological function as natural porcine type I IFN.
cord-327000-oyg3oyx1	2020	This review highlights the immune evasion mechanisms employed by PEDV, which provides insights for the better understanding of PEDV-host interactions and developing effective vaccines and antivirals against CoVs. Porcine epidemic diarrhea virus (PEDV) is the etiological agent of porcine epidemic diarrhea (PED) that causes an acute and highly contagious enteric disease of swine characterized by vomiting, diarrhea, dehydration, and anorexia in pigs of all ages, especially resulting in severe diarrhea and high mortality rate in piglets. Nsp3 is the largest nsp protein, containing two papain-like protease (PLP1 and PLP2) domains, of which PEDV PLP2 acts as a viral deubiquitinase (DUB), to negatively regulate type I IFN signaling [80] . The evasive strategies utilized by PEDV are classified into four major types: (1) inhibition of RLRs-mediated IFN production pathways, (2) inhibition of the activation of transcription factors responsible for IFN induction, (3) disruption of the signal cascades induced by IFN, and (4) hiding its viral RNA to avoid the exposure of viral RNA to immune sensors.
cord-327135-4c2flue4	2016	Interferon (IFN) lambda (IFN-λ or type III IFN) gene polymorphisms were discovered in the year 2009 to have a strong association with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection in human hosts. Three independent groups conducted genome-wide association studies (GWASs) involving treatment response to chronic hepatitis C virus (HCV) infections, in three different geographical regions of the world, and reported that single-nucleotide polymorphisms (SNPs) in the IFNL locus (Figure 1 ), had strong association with treatment-induced HCV clearance irrespective of ethnicity and geographical location of the hosts. 49 In stark contrast, a dominant model of inheritance (of the non-beneficial IFNL SNP minor allele) has consistently given the best explanation on the observed phenotypes in association studies with both spontaneous clearance and IFN-based treatment response in chronic HCV infections.
cord-327534-f2wvh6la	2014	
cord-327685-fymfqvp3	2017	In contrast, highly pathogenic hCoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) predominantly infect lower airways and cause fatal pneumonia. Severe pneumonia caused by pathogenic hCoVs is often associated with rapid virus replication, massive inflammatory cell infiltration and elevated pro-inflammatory cytokine/chemokine responses resulting in acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Although there is no direct evidence for the involvement of pro-inflammatory cytokines and chemokines in lung pathology during SARS and MERS, correlative evidence from patients with severe disease suggests a role for hyper-inflammatory responses in hCoV pathogenesis. Infection of non-human primates (NHPs) with SARS-CoV induced a dysregulated immune response resulting in increased disease severity in aged but not young NHPs, despite similar viral titers in the airways [67] . T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice
cord-327855-txryqil7	2003	Analysis of total cellular RNA from HM175/18f infected FrhK4 cells by denaturing agarose gel electrophoresis and Northern blot hybridization revealed extensive degradation of both the 28S and 18S ribosomal RNA (rRNA) molecules. In this study, we report that infection of FrhK4 cells with the HAV cp strain HM175/18f results in the degradation of ribosomal RNA (rRNA) and the reduction of several cellular mRNAs including β-actin and GAPDH. Degradation of rRNA is a feature of virus infection in interferon (IFN) treated cells and is believed to be due to the availability of double stranded RNA (dsRNA) during replication or transcription of the viral genome, resulting in the activation of the RNase L pathway [58, 59] . While the role of a viral protein in the activation of 2-5A/RNase L pathway in 18f or CBV1 infected FrhK4 cells cannot be ruled out, previous reports with EMC virus and the studies involving dsRNA clearly suggests a similar mechanism of rRNA degradation reported here.
cord-328252-dk54w8z9	2019	Whether PA-X also degrades viral dsRNA species to prevent recognition by cytosolic RNA sensors is not entirely clear, but mutant viruses in which this PA-X protein was expressed in significantly lower amounts elicited higher levels of innate immune response; for example, IFN-beta production was much higher in these infections [71] . This indeed suggests that PA-X, besides having a role in the degradation of cellular mRNAs, may also degrade viral RNA to prevent recognition by innate immune sensors and activation of innate immune responses, similar to what was shown for the CoVs. To my knowledge, an endoribonuclease has not been identified in the RSV genome, so this virus may use alternative innate immune evasion strategies, as discussed elsewhere in this review. [91] suggested that RSV specifically targets mRNA encoding surfactant protein A, an innate immune factor with an important role in the epithelial tissue of the lung, which directly binds to virus particles to cause their destruction by host defense mechanisms.
cord-328804-f7etlk5i	2007	Hence, global gene-expression profiling on inguinal lymph nodes was performed 10 days after the induction of pristane-induced arthritis (PIA) and phytol administration. To analyze the in vivo effects of the NADPH oxidase activator phytol versus the effects of the arthritis-inducing compound pristane, global gene-expression profiling was performed. By studying gene-expression profiles and performing pathway analysis, we have identified the importance of an IFN-β-dependent pathway as one molecular mechanism for the arthritis-ameliorating efficacy of NADPH oxidaseactivating compounds. To obtain a more detailed understanding of the molecular mechanism of this regulation, gene-expression profiling experiments were performed on inguinal lymph nodes from rats with pharmacologically (phytol) and genetically (Ncf1) modified NADPH oxidase activity. In this study, we used global gene-expression analysis and quantitative real-time PCR techniques in four separate arthritis experiments in rats to investigate the downstream effects of preventive arthritis treatment with the NADPH oxidase activator phytol.
cord-328947-3l9ydspz	2020	CHIKV is no exception, the type-I interferon (IFN) response has been demonstrated to be key in controlling CHIKV infection [21] [22] [23] [24] [25] [26] and primary sensing of the virus is via the pattern recognition receptor (PRR) retinoic acid-inducible gene I (RIG-I)-mitochondrial antiviral signaling protein (MAVS) axis [24, 26] . The lack of cGAS degradation seen in the exogenous expression system when compared to the infected cells shows that although there is a clear interaction of cGAS with nsP4, the degradation of cGAS observed is not mediated by the non-structural proteins of CHIKV, but must require other viral or host factors. Chikungunya virus inhibits DNA sensing by degrading cGAS both mock and infected cells by 4 hpi suggesting that the stress produced during the process of infection (mock or CHIKV) in HFF-1s stimulates increased translation at early timepoints ( Fig 4D, lanes 2 and 5) .
cord-329190-kv9n2qj3	2017	The current therapies have mainly been adapted from severe acute respiratory syndrome (SARS-CoV) treatments, including broad-spectrum antibiotics, corticosteroids, interferons, ribavirin, lopinavir–ritonavir or mycophenolate mofetil, and have not been subject to well-organized clinical trials. The Medline database was searched using combinations and variations of terms, including ''Middle East respiratory syndrome coronavirus'', ''MERS-CoV'', ''SARS'', ''therapy'', ''molecular'', ''vaccine'', ''prophylactic'', ''S protein'', ''DPP4'', ''heptad repeat'', ''protease'', ''inhibitor'', ''anti-viral'', ''broad-spectrum'', ''interferon'', ''convalescent plasma'', ''lopinavir ritonavir'', ''antibodies'', ''antiviral peptides'' and ''live attenuated viruses''. A position paper on the evidence base for specific MERS-CoV therapies, published by Public Health England (PHE) and the World Health Organization-International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC-WHO), suggested that benefit was likely to exceed risk for convalescent plasma, lopinavir-ritonavir, IFNs and monoclonal/polyclonal antibodies, while, by contrast, for ribavirin monotherapy and corticosteroids it was considered that the risks would outweigh the benefits [42] .
cord-329366-xuszdrsa	2020	In this study, we show that CoV EndoU activity limits the abundance and length of the polyuridine (polyU) extension on 5′-polyU-containing, negative-sense (PUN) RNAs for both the beta-CoV mouse hepatitis virus strain A59 (MHV-A59) and the alpha-CoV PEDV. Overall, we propose a mechanism for EndoU, which is to cleave polyU sequences from PUN RNAs, thus limiting the formation of a PAMP and impeding the ability of MDA5 to activate the innate immune response to infection. EndoU Activity Limits Abundance and Length of PUN RNAs. Previous studies showed that the 5′ end of the CoV negative-sense RNA contains polyU extensions (35) , and that EndoU cleaves at uridine residues (22, 25, (27) (28) (29) (30) . We found that the products generated from positive-sense RNA were similar between wild-type and EndoUmut viruses, consistent with our previous results indicating that the polyA tail is not cleaved by EndoU activity (Fig. 5C ).
cord-329424-hmsidrc7	2020	
cord-329618-kywhulpc	2016	To elucidate the effect of type I IFN on the Jak/stat pathway in salmonid alphavirus subtype 3 (SAV3) infected macrophage/dendritic like TO-cells derived from Atlantic salmon (Salmo salar L) headkidney leukocytes, we used a differential transcriptome analysis by RNA-seq and the Kyoto encyclopedia of genes and genomes (KEGGs) pathway analysis to generate a repertoire of de novo assembled genes from type I IFN treated and non-treated TO-cells infected with SAV3. CONCLUSION: Data presented in this study shows that SAV3 infection downregulates several genes of the Jak/stat pathway, which could be an immune evasion strategy, used to block the transcription of antiviral genes that would interfere with SAV3 replication in TO-cells. Hence, in this study we used the KEGG pathway analysis software which is a third generation PT based software to identify networks of genes that form the Jak/stat signaling pathway from a de novo assembled transcriptome with the aim to better understand the modulation of genes expressed by TO cells infected with SAV3.
cord-330176-1ugzkf22	2016	In vitro, an effective dose of Angelica tenuissima Nakai markedly inhibited the replication of Influenza A virus (PR8), Vesicular stomatitis virus (VSV), Herpes simplex virus (HSV), Coxsackie virus, and Enterovirus (EV-71) on epithelial (HEK293T/HeLa) and immune (RAW264.7) cells. To investigate the antiviral effects in immune cells, we first assessed the replication of divergent GFP-expressing viruses that were treated or untreated with cytotoxic-free (data not shown) Angelica tenuissima Nakai in RAW264.7 cells. These results suggest that the aqueous extract of Angelica tenuissima Nakai can induce the secretion of IFNs and pro-inflammatory cytokines, which can stimulate the cellular antiviral state for inhibition of viral replication. The aqueous extract of Angelica tenuissima Nakai inhibit the diverse viral infection through the induction of Type I IFN signaling and pro-inflammatory cytokines, leading to an antiviral state in epithelial and immune cells.
cord-332071-bqvn3ceq	2020	
cord-332154-2gej7h1d	2004	Immunization of pigs with a modified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine initially elicits a weak interferon (IFN)-γ response. Based on the success of this intervention and the noted absence of IFN-a generation during PRRSV infection, the present studies were undertaken to determine if the antiviral adaptive immunity induced by vaccination with PRRS MLV could be modified simply by the co-administration of rIL-12 protein directly, or of either porcine IFN-a or IL-12 indirectly via plasmids expressing these cytokines. Although a similar response was evident during this time period for vaccinated pigs also i.m. injected with exogenous IL-12 either directly as protein or indirectly via IL-12 cDNA, immunized animals that were i.d. inoculated with IL-12 cDNA exhibited an overall 2.7-fold transient increase in the frequency of PRRSV-specific IFN-g SC at 2 weeks post-vaccination. Immune responses in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV)
cord-332632-u2ud0vmq	2016	In particular, the unique extension of ''self'' to include the viral genome by degrading immunostimulatory viral RNA by E(rns) is reminiscent of various host nucleases that are important to prevent inappropriate IFN activation by the host''s own nucleic acids in autoimmune diseases such as Aicardi-Goutières syndrome or systemic lupus erythematosus. Thus, the survival strategy of BVDV consists of being non-cytopathogenic and producing less dsRNA than its cp counterpart, and expressing the IFN antagonists N pro as the first protein in order to reduce or even avoid IFN production in infected cells and E rns to degrade immunostimulatory viral RNA before they might activate the host''s PRRs. Notably, both pestiviral IFN antagonists are not only required to constantly maintain innate immunotolerance during persistent infections, but they also play an important role in acute infections [25] .
cord-332688-xqt2aw96	2020	
cord-333208-tibtngy8	2016	The interferon-induced transmembrane (IFITM) protein family is a group of antiviral restriction factors that impair flexibility and inhibit membrane fusion at the plasma or the endosomal membrane, restricting viral progression at entry. The role of IFITM2 in the inhibition of ASFV in Vero cells could be related to impaired endocytosis-mediated viral entry and alterations in the cholesterol efflux, suggesting that IFITM2 is acting at the late endosome, preventing the decapsidation stage of ASFV. Thus, our goal in the current work was to test whether the IFITM family of proteins affected early entry steps of ASFV infection in Vero cell cultures using the cell-adapted Ba71V isolate. Confocal microscopy experiments revealed that, IFITM1 was mainly distributed at the plasma membrane and to a lesser extent in perinuclear compartments, resembling endosomal structures (Fig 3C, lower left panel) , while endogenous IFITM1 was barely detected in Vero cells containing the empty vector (Fig 3C, upper left panel) .
cord-333286-lr32e0w4	2020	
cord-333423-jhm7u8ka	2019	Furthermore, the nsp11-IRF9 interaction impaired the formation and nuclear translocation of the transcription factor complex IFN-stimulated gene factor 3 (ISGF3) in both nsp11-overexpressed and PRRSV-infected cells. Taking the results together, our study demonstrated that PRRSV nsp11 antagonizes type I IFN signaling by targeting IRF9 via a NendoU activity-independent mechanism, and this report describes a novel strategy evolved by PRRSV to counteract host innate antiviral responses, revealing a potential new function for PRRSV nsp11 in type I IFN signaling. The type I IFN-activated ISGF3 transcription complex containing tyrosine-phosphorylated STAT1 and STAT2 associated with IRF9 is rapidly translocated to the nucleus FIG 3 PRRSV nsp11 inhibits ISGF3-induced ISRE promoter activity. This provided further support for the notion that the ability of PRRSV nsp11 to block type I IFN signaling is independent of its endoribonuclease activity and cell cytotoxicity, because these three mutants had similar effects with respect to inhibiting the formation and nuclear translocation of ISGF3 compared with WT nsp11.
cord-333463-u7je0d1o	2020	Nearly all emerging viruses, including Ebola, Dengue, Nipah, West Nile, Zika, and coronaviruses (including SARS-Cov2, the causative agent of the current COVID-19 pandemic), have zoonotic origins, indicating that animal-to-human transmission constitutes a primary mode of acquisition of novel infectious diseases. Natural killer (NK) cells are innate lymphocytes that play a critical role in the early antiviral response, secreting effector cytokines and clearing infected cells. This review describes the role of Natural killer (NK) cells, a critical component of early antiviral immunity, in the establishment of tolerance to viral infections in natural hosts, as well as their role in the development of disease in nonnatural hosts. Altogether, it is believed that quick control of viral infections and reduced induction of pro-inflammatory cytokines have allowed bat viruses to rapidly co-evolve with their host without provoking major immuneThe careful study of the immune system in reservoirs of zoonotic diseases will certainly offer insights into how these animals carry high viral loads while remaining asymptomatic.
cord-333600-k6ws97at	2020	Host control of MHV infection is completely dependent on TLR7 triggering by viral RNA causing an immediate interferon (IFN) response [2] . Sex differences in TLR7 responses have been reported for humans -with female sex better coping with viral infection [4] [5] [6] -which is also a feature of COVID-19. Upon binding viral nucleic acid motifs, TLR7 induces the expression of type I IFNs (IFN-α and IFN-β) and the expression of the more recently described family of type III IFNs (IFN-λ [1] [2] [3] [4] . A common germ line genetic variation within the type III IFN gene locus has been most convincingly shown to determine the host''s capacity to cope with an infection induced by hepatitis C virus (HCV), an enveloped ssRNA virus of positive orientation, too, featuring tropism for liver epithelial cells. CD200 receptor controls sex-specific TLR7 responses to viral infection IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes
cord-333650-4towah1t	2016	Overall, our data point to cytokines, particularly inflammasome-associated, that might be important in hMPV mediated lung disease and the antiviral response in children with severe infection. To determine the presence of antiviral cytokines in children infected with hMPV and controls, we initially investigated the expression of type I, II and III IFNs. Fig 1A shows that only A2 infected children had slightly elevated mRNA levels of the type I IFN-β compared to the controls. Fig 2 shows the mRNA expression of A) IκBα, a repressor gene induced by NF-κB activation [19] , B) IL-1β, C) IL-18 and D) NLRP3 in hMPV infected children and controls. A previous study comparing the expression of several inflammatory cytokines in hMPV, RSV and influenza virus, detected elevated levels of TNF-α, IL-6 and IL-1β protein in nasal washes from infants with RTI [9] .
cord-333955-bnzbppof	2011	Here, we investigated interferon (IFN) response, -induction, -secretion and -signaling in epithelial-like cells of the relevant and abundant African fruit bat species, Eidolon helvum (E. Cells from Pteropus species have been shown to produce high amounts of interferon (IFN)-l after stimulation with the double-strand (ds)RNA analogue poly IC, and after infection with the bat-associated paramyxovirus, Tioman [13] . In accordance with the IFN mRNA induction, the highest equivalent amount of bioactive secreted IFN upon RVFV 13 virus infection and poly IC transfection was measured in EidNi/41.3 cells, followed by MEF and MA104 (Figure 3 ). Increases of infectious virus formation were about 1000-fold within 24 hpi, and specific infectivities, expressed as PFU per genome equivalent (PCR units), were highly comparable between cell cultures ( Figure 4C) .
cord-334134-fhie2m3u	2012	We assessed the effect of triggering TLR2, TLR3, TLR4, and TLR7 with selected ligands on the susceptibility of the J774A.1 macrophage cell line to infection with murine coronavirus (mouse hepatitis virus, [MHV]). These results together with the antiviral effect of poly I:C (Figure 3 ) suggested that the protective role of TLR3 against coronavirus infection in J774A.1 macrophages may be mediated by type I IFN. We hypothesized that the differential effect of TLR ligands on MHV production is due to their variable ability to induce type I IFN crucial for triggering an "antiviral state" and protecting cells from virus infection [26, 38] . In the present study prestimulation of J774A.1 macrophages with poly I:C, a potent type I IFN inducer, resulted in a strong IFN-β response that triggered antiviral immunity and protected macrophages from MHV infection before and after virus adsorption.
cord-334510-37g8zxne	2014	OBJECTIVE: To study intratonsillar/nasopharyngeal virus detections and in vivo expressions of T‐cell‐ and innate immune response‐specific cytokines, transcription factors, and type I/II/III interferons in human tonsils. Conclusions: Tonsillar cytokine expression is closely related to existing viral infections, age, and allergic illnesses and shows distinct clusters between antiviral and immune regulatory genes. Conclusions: Tonsillar cytokine expression is closely related to existing viral infections, age, and allergic illnesses and shows distinct clusters between antiviral and immune regulatory genes. Studies in adults have shown an association between persistent/latent Abbreviations AdV, adenovirus; BoV, bocavirus-1; CT, cycle threshold; CV, coronavirus; EF1-a, elongation factor-1a; EV, enteroviruses; FOXP3, forkhead box protein 3; Flu, influenza A or B virus; IFN, interferon; IL, interleukin; MPV, metapneumovirus; PBMC, peripheral blood mononuclear cells; PCR, polymerase chain reaction; PIV, parainfluenza virus types 1-4; RORC2, retinoic acid receptor-related orphan receptor C2; RSV, respiratory syncytial virus; RV, rhinovirus; suppl., supplementary; Th, T helper cell; TGF-b, transforming growth factor-b.
cord-334624-chnibsa1	2020	Here, we systematically assessed the impact of 29 SARS-CoV-2 proteins on viral sensing, type I, II and III interferon (IFN) signaling, autophagy and inflammasome formation. Our results identify ineffective type I and II antagonism as weakness of SARS-CoV-2 that may allow to devise safe and effective anti-viral therapies based on targeted innate immune activation. SARS-CoV-1 ORF6 is about 4-fold less potent in antagonizing type I IFN signaling (Fig. 243 4b) but induces higher levels of autophagy (Fig. 4c) . Examination of the functional conservation showed that SARS-CoV-2 Nsp15 was less 319 efficient in blocking innate immune activation, both type I IFN induction and signaling, than SARS-320 Hepatitis C virus viruses to block anti-viral autophagic turnover 50 and thus may represent a common studies will see more mechanistic data to explain the molecular details of the impact of SARS-CoV-2 343 proteins on innate immune activation.
cord-335245-1eksm537	2008	Western blot analysis visualized more efficient conjugation of OWmISG15 relative to HuISG15 in human (Hu), monkey and mouse (Mo) cell-lines. Western blot analysis on total cell lysates containing b-ME confirmed ISGylation of UbcH10, H13 and H17 with AgmISG15 but not with HuISG15, as seen by a 15 kDa shift upon staining with anti-V5 Ab detecting the ectopic expressed UbcH proteins (Figure 3a ,b and Figure S2a ). Previous studies using Western blot analysis in HekT cells revealed Hu or MoISG15 conjugation to substrates such as UbcH13 only upon co-transfection of at least UbE1L -and generally also UbcH/M8or upon IFN stimulation. The effect of mutating HuISG15 residues situated near the predicted UbE1L interface and the different allelic variants on conjugation to UbcH proteins is shown in Figure 5a and S3a. As shown in Figure 5c , mutation of D133N and QIT31-33KIA in the HuISG15 N89D variant further enhanced its ISGylation in human HekT cells.
cord-335384-co2fgz26	2017	These differential responses were not dependent on the dose of agonist used to stimulate microglia, as increasing the doses of TLR ligands did not result in enhanced secretion of IL-10, nor of TNF (Supporting Information, Figure 1 ). Considering the cytokine landscape obtained upon TLR3 triggering of microglia (Figure 1 ), if such mechanism was operating, the best candidate molecule would be IFN-b, as it is strongly induced by TLR3 ( Figure 1g ) and it has been described to potentiate IL-10 in studies performed with bone marrow-derived macrophages and dendritic cells (Iyer, Ghaffari, & Cheng, 2010; F. Co-stimulation of microglia with TLR3 enhanced IL-10 production via IFN-b, thus opening a novel mechanism underlying its beneficial role in MS and being a possible tool to locally regulate inflammatory responses.
cord-336510-qzm9wgde	2005	
cord-337285-t6qr41wc	2007	Using cell culture systems, several cellular proteins have been identified as effective molecules for HCV RNA replication (Table 1) . [66] reported that lovastatin (LOV), one of the HMG-CoA reductase inhibitors, inhibited HCV RNA replication in HCV replicon-harboring cells. Depletion of the GGPP by statins may inhibit the geranylgeranylation of cellular proteins such as FBL2 and cause the anti-HCV effect in the cells. During the development of IFN therapy for patients with CH-C, the lack of a robust method of HCV RNA replication in cell culture has hampered research into the HCV life cycle and the discovery of potent new anti-HCV reagents. VX-950, a novel hepatitis C virus (HCV) NS3-4A protease inhibitor, exhibits potent antiviral activities in HCV replicon cells Selectable subgenomic and genome-length dicistronic RNAs derived from an infectious molecular clone of the HCV-N strain of hepatitis C virus replicate efficiently in cultured Huh7 cells
cord-337365-hugenn14	2019	Microglia can exert a direct antiviral effect by producing type 1 interferon (IFN-1) to induce IFN-stimulated gene (ISG) expression of themselves or indirect antiviral effects by IFN-1 acting on other cells to activate corresponding signaling pathways. In a mouse model of West Nile virus (WNV) infection, it was found that the permeability of the BBB increased in mice lacking IFNAR, especially in the hindbrain, which leads to an increase in viral entry, indicating that IFNAR signaling has important regulatory effects on BBB permeability in this brain region. Loss of astrocyte IFNAR signaling pathway can cause a variety of consequences, including increased expression of inflammatory cytokines and chemokines, which disrupt the blood-brain barrier during neurotropic viral infection [30] . In a mouse model of lethal West Nile virus (WNV) infection, Peli1 promotes the production of pro-inflammatory cytokines and chemokines in microglia and promotes the entry of T cells and macrophages into the CNS.
cord-337458-dc90ecfe	2018	In this review, we define the components of a diagnostic to include: (1) the target biomarker, an endogenous indicator of a disease state, which is most often a pathogen or host protein, carbohydrate, or nucleic acid sequence, (2) sample preparation, which allows for biomarker isolation, purification, and/or concentration from complex biological matrices, (3) molecular recognition elements, which specifically capture and detect the target biomarker, (4) signal generation and amplification, and (5) instrumentation for signal read-out. 113, 114 In subsequent studies, the group developed and optimized a hand-held, easy-to-use device 85, 115 (Figure 8A ) in which HRP2-bound, IMAC-functionalized magnetic beads were directly transferred to the sample pad of commercial malaria lateral flow assays. If combined with one of the sample preparation strategies discussed previously (section 3) or integrated with paper or another field-ready substrate, this Ir(III)-based detection strategy could produce a robust and sensitive assay that is applicable in low-resource diagnostic settings.
cord-337677-ktktqs7b	2020	Patients received therapy as per the Cuban COVID protocol that included a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular or subcutaneous administration of IFN alpha-2b The primary endpoint was the proportion of patients discharged from hospital, secondary was the case fatality rate and several outcomes related to time variables were also evaluated. Two groups of individuals were admitted to the hospital, according to the case classification criteria defined in the Cuban protocol: 1) people with suspected COVID-19 due to clinical respiratory symptoms, such as fever, fatigue, cough, headache, shortness of breath and nasal discharge in the last 14 days; 2) subjects who had contact with a patient with confirmed or is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint
cord-337717-8hcujmuo	2012	CNS inflammatory conditions were selectively manipulated by adoptive transfer of virus-primed wild-type (WT) or IFN-γ deficient (GKO) memory CD4(+) T cells into infected SCID mice, coupled with antibody-mediated neutrophil depletion and cytokine blockade. RESULTS: Transfer of GKO memory CD4(+) T cells into infected SCID mice induced rapid mortality compared to recipients of WT memory CD4(+) T cells, despite similar virus control and demyelination. Overall these data confirm IFN-γ-mediated control of CNS neutrophil infiltration and suggested a protective role of IFN-γ during viral encephalitis, via inhibiting IL-17 effector function by either directly reducing Th17 cell expansion and/or CNS entry, or limiting GM-CSF production. Although GM-CSF expression is reduced by IFN-γ [27] , the data do not support a pathogenic role of GM-CSF in early mortality of JHMV-infected GKO recipients.
cord-338320-jc00ulx5	2014	title: Suppression of innate antiviral response by severe acute respiratory syndrome coronavirus M protein is mediated through the first transmembrane domain We have previously shown that severe acute respiratory syndrome (SARS) coronavirus M protein suppresses type I interferon (IFN) production by impeding the formation of functional TRAF3-containing complex. 12 , 13 We have previously reported that SARS coronavirus M protein suppresses type I IFN production potently by preventing the formation of functional TRAF3-TANK-TBK1/IKKe complex. IFN antagonism of SARS coronavirus M protein was mediated by N-terminal TM1 (amino acids 1-38), which targets M protein to the Golgi complex and associates with TRAF3 to prevent it from interacting with TANK, TBK1 and IKKe. Our findings provide additional molecular details for suppression of type I IFN production by SARS coronavirus M protein. Notably, human coronavirus HKU1 M protein also targets the Golgi complex, interacts with TRAF3, but does not suppress IFN production.
cord-338602-6n309bnp	2020	title: IFN-γ is an independent risk factor associated with mortality in patients with moderate and severe COVID-19 infection We proposed a study in patients with moderate to severe COVID-19 infection to evaluate the interleukin patterns and its role as prognosis factors. A reasonable hypothesis is that (i) pro-inflammatory innate immunity and (ii) anti-inflammatory system are related to disease severity or death once IL-6, IL-8, and IL10 are closely described as prognostic factors in patients diagnosed with COVID-19 1, 3, 7 . Previous studies have not reported the association between IFN-γ and death, even evaluating the COVID-19-reactive CD69+ expressing IFN-γ producing CD8+ T in 25 patients with severe and moderate disease 22 . Suppressed T cell-mediated immunity in patients with COVID-19: A clinical retrospective study in Wuhan Levels of cytokines from patients with moderate and severe COVID-19 infection according to the outcome (data in the median with IQR)
cord-339991-k8z6v2vx	2003	UV-inactivated, infectious, and other forms of herpes simplex virus 1 (HSV-1) induced interferon (IFN) production by different routes in myeloid origin mononuclear cells (MOMC) (consisting predominantly of monocytes). Comparison of the activities of different strains of infectious HSV, UV-inactivated HSV, and a mutant HSV incapable of penetration (K T) [9] and results of treatment with a mannose receptor antagonist indicate that there are more than one mechanism for HSV induction of interferon in the MOMC origin cell populations. The greater response to UV-inactivated virus suggests that non-infectious virions and possibly HSV infected cell debris are the more potent activators of IFN α production and that replicating virus can limit the induction of interferon production as a means of escaping host protection. Interferons and the colony-stimulating factors IL-3 and GM-CSF enhance the ifn-alpha response in human blood leucocytes induced by herpes simplex virus
cord-340422-8f5xe4zc	2001	Porcine reproductive and respiratory syndrome virus (PRRSV) belongs to a group of RNA viruses that establish persistent infections. IFN-γ mRNA expression was observed in the lymph nodes and lungs of pigs infected with wild-type PRRSV strain SDSU-23983. The purpose of this study was to evaluate the production of IFN-␥ in pigs following infection with PRRSV and to characterize the mechanism of IFN-␥ action following infection of MARC-145 cells with wild-type and culture adapted PRRSV isolates. The results show that IFN-␥ efficiently inhibits PRRSV replication in MARC-145 cells, and at least part of the antiviral activity may be through PKR. IFN-␥ mRNA expression was detected in the lymph nodes from two of the 3 pigs infected with the wild-type P6 virus (Fig. 1) . Consistent with other reports describing the presence of cell-mediated immunity during PRRSV infection [4, 31] , we observed IFN-␥ mRNA expression in lymph nodes and lungs of PRRSV-infected pigs (Fig. 1) . IFN gamma inhibits porcine reproductive and respiratory syndrome virus replication in macrophages
cord-340475-h0q1m3ed	2014	Further validation showed that ISR2, 8, and 12 expression mimics that of their neighboring genes GBP1, IRF1, and IL6, respectively, all related to the IFN response.These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8) or later (ISR12) time points. HuH7 cells were treated for 6, 24, 48, or 72 h with increasing doses of IFNα2 up to 10,000 units/ml, and the expression levels of GBP1, IRF1, BST2, OAS, IL6, and ISG15 were evaluated by qRT-PCR (Figure 1) .
cord-341278-klv9jdm8	1991	Infection of BALB/c mice with mouse hepatitis virus, strain JHM (MHV-JHM), at any of several intervals relative to ovalbumin (OVA) administration resulted in elevated OVA-specific IgG 2 a titers. Serum IFN-γ was not detected, but treatment of MHV-JHM-infected mice with monoclonal anti-IFN-γ antibody resulted in high mortality with decreased survival times, enhanced virus titers in liver and spleen, and more severe virus-associated pathology, compared to mock-treated, infected mice. Sera from mice infected with MHV-JHM one day prior to OVA administration contained substantially elevated levels of antigen-specific IgG2 a on day 7 (Table 1 ) with geometric mean titers that were 17 times control (OVA only) values at that interval. The elevated IgG 2 a OVA-specific response of most groups of MHV-infected mice and the preferential production of this isotype by mice infected one day prior to antigen administration suggested that these mice were producing IFNy. However, using the WEHI 279 B cell lymphoma bioassay [24] , attempts to detect the cytokine in sera of infected mice failed, as had earlier attempts to 27] .
cord-341324-f9g9gitn	2020	This includes for instance cooperating in PRR recognition of viral PAMPs, stabilizing signaling complexes to improve their resistance to degradation, stopping virus entry, blocking viral capsid formation, impairing trafficking and budding of virions from the infected cells, but also modulating the IFN response to avoid the toxicity of these potent immune mediators. The phosphorylated STAT1/STAT2 heterodimer associates with interferon regulatory factor 9 (IRF9) to form the transcriptional factor complex ISGF3, which translocate to the nucleus and binds the IFN-response elements (ISRE) in ISG promoters leading to the expression of ISG products [36] (Fig. 2 The oligoadenylate synthetase (OAS)-latent RNase (RNase L) pathway is another IFN-inducible pathway that provides the cell with an effector mechanism upon recognition of viral dsRNA (reviewed in [44] ).
cord-341478-bicg5ozr	2002	To explore the regulated transgene expression in the context of a helper-dependent vector, we constructed the HD-TET-IFN vector, containing the mIFNα gene under the control of the tetracycline inducible transactivator rtTA2(s)-S2. In addition, C57/B6 mice injected at low HD-TET-IFN doses resulted in Doxmediated regulation of liver restricted mIFN␣ expression, which was associated with induction of antiviral genes. These results indicate that HD-TET-IFN allowed a significant expression of mIFN␣ controlled in vitro by Dox. To verify the efficiency and persistence of mIFN␣ secretion, C57/B6 mice were injected i.v. with 1.4 × 10 10 pp of HD-IFN or HD-TET-IFN and the mIFN␣ released in the serum was measured over time. C57/B6 and Balb/C mice were i.v. injected with different doses of HD-TET-IFN and mIFN␣ measured at day 21 p.i. after a treatment for 3 days with Dox, 200 g/ml, present in the drinking water (Figure 7a ).
cord-341822-uk6kvxyd	2016	
cord-342063-1si0qrrx	2020	They reported 311 patients with acral lesions occurring during the COVID‐19 lockdown in France. They concluded that there is no evidence of SARS‐CoV‐2 infection in the large majority of patients with acral lesions. They reported 311 patients with acral lesions occurring during the COVID-19 lockdown in France. They concluded that there is no evidence of SARS-CoV-2 infection in the large majority of patients with acral lesions. They hypothesized that the situation could be due to the media stating that chilblains were caused by SARS-CoV-2 infection and leading to a higher rate of consultation or the lockdown leading to more inactivity and long periods at home barefoot on a cold floor 1 . Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on PCR and serology testing
cord-342189-ya05m58o	2020	Here, we comprehensively define the interactions between each SARS-CoV-2 protein and human RNAs. We show that 10 viral proteins form highly specific interactions with mRNAs or ncRNAs, including those involved in progressive steps of host cell protein production. We show J o u r n a l P r e -p r o o f 5 that NSP16 binds to the mRNA recognition domains of the U1 and U2 RNA components of the spliceosome and acts to suppress global mRNA splicing in SARS-CoV-2-infected human cells. We identified several pathogenic functions of SARS-CoV-2 in human cells -including global inhibition of host mRNA splicing, protein translation, and membrane protein trafficking -and described the molecular mechanisms by which the virus acts to disrupt these essential cell processes.
cord-342800-62jklwiy	2020	The RNActive ® vaccine platform designed by CureVac used co-delivered RNA and protamine complex as the adjuvant to induce Th1 T cell responses, and naked, unmodified, and sequence-optimized mRNA as the antigen to develop mRNA vaccines [54] . used LNP to deliver self-amplified RNA vaccines, which caused the mRNA expression level in mice to be significantly higher than that of naked mRNA, CD4 + , and CD8 + T cell immune responses were also effectively induced. Overall development steps of those vaccines are (1) constructing the core antigen-encoding mRNA sequence optimized or combined based on selected antigen(s) from the target pathogen; (2) trying and choosing a proper combination of mRNA construction type, adjuvants, carrier materials and the route of administration; (3) detecting in vivo expression of the encoded antigen and the level of elicited immune responses; (4) providing research and demonstrations of immune induction mechanisms.
cord-343221-e29of29o	2017	Specifically, we show that genetically engineered mutants of mouse hepatitis virus (MHV) and human coronavirus 229E (HCoV-229E), respectively, that encode an EndoU active-site substitution known to abolish nucleolytic activity, were severely attenuated and elicited an immediate and simultaneous activation of host cell dsRNA sensors. The severe attenuation of MHV H277A and HCoV-229E H250A replication in wild-type murine and human macrophages, respectively, precluded the use of primary macrophages to assess the sensitivity of EndoU-deficient coronaviruses to IFN-I pre-treatment. Our data suggest that direct restriction of replication of EndoU-deficient coronaviruses is mediated by RNase L-mediated RNA degradation and inhibition of host cell translation through activation of PKR. Notably, also in this case Xrn1 is required to further process the de-capped mRNAs. Our data show that early during coronavirus infection the EndoU activity conceptually fulfils the same task, namely the removal of dsRNA that would otherwise trigger host cell dsRNA responses, such as IFN-β expression and activation of PKR and OAS/RNase L.
cord-343515-fad1yyqx	2020	For SARS-CoV-2 (dark gray bars), statistically significant negative correlation coefficients (CC) were obtained for both cell lines, indicating that viral replication is increasingly inhibited by IFN-a. Observations were similar when the input MOI was reduced to 0.001 (Fig. S1 ), except that titers of SARS-CoV-1 in Calu-3 cells were already very low in the absence of any IFN-a, resulting in a nonsignificant effect of additional IFN. Our data thus indicate that (i) if anything, ruxolitinib is an enhancer rather than an inhibitor of SARS-CoV-2 multiplication, and (ii) the boosting effect is most likely due to inhibition of the antiviral JAK/ STAT signaling pathway, because it is not present in the IFN induction-deficient Vero E6 cells. For the statistical testing of the dose-response effect of IFN (type I and III) against SARS-coronaviruses, the typical regression procedures were not applicable because of several values below the detection limit and some ties in the data.
cord-343824-00mqmpzw	2017	title: The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-β Production by Targeting TNF Receptor-Associated Factor 3 Influenza A virus non-structural protein 1 (NS1) antagonizes interferon response through diverse strategies, particularly by inhibiting the activation of interferon regulatory factor 3 (IRF3) and IFN-β transcription. Hence, binding of the NS1 protein to dsRNA, RIG-I, and TRIM25 has not established that these NS1 interactions are responsible for inhibiting the activation of IRF3 and IFN transcription. These data reveal a novel mechanism for how the influenza A virus NS1 protein induces inhibition of the host IFN production and may provide a potential target for antiviral drug development. However, our study demonstrated that the influenza A virus NS1 ED targets TRAF3, subsequently inhibits IFN production, implying that TRAF3 is a key factor involved for IAV to escape host innate immune responses.
cord-343963-99rd3o79	2014	13, 14 Upon infection by viruses such as HCV, viral RNA is first sensed by cellular pattern recognition receptors (PRRs), and the PRR-mediated recruitment of adaptor proteins and the activation of downstream signaling lead to IFN production. First, we briefly discuss the signaling triggered by the retinoic acid-inducible gene 1-like receptor (RLR) and the Toll-like receptor (TLR), which leads to type I IFN synthesis and IFN-mediated signaling pathway activation, resulting in the expression of a variety of effector ISGs. We also summarize the strategies that HCV uses to escape IFN antiviral surveillance. 156 demonstrated that HCVinduced SG formation is IFN-and PKR-dependent and is inversely correlated with the induction of ISG proteins, such as myxovirus resistance gene A (MxA) and Ub-like (UBL)specific protease 18 (USP18), in HCV-infected cells without affecting the mRNA levels of these ISGs. Furthermore, the SG proteins TIA-1, TIAR and G3BP1 have been shown to play a critical role in HCV replication and infectious virus production.
cord-344093-3bniy5b5	2017	A prominent regulator of disease outcome, especially in-but not limited to-respiratory viral infection, is the IFN-dependent mediator TRAIL (TNF-related apoptosis-inducing ligand) produced by several cell types including immune cells such as macrophages or T cells. (73) Cell death induction, e.g., Bcl-2-associated X protein, caspase-8, Fas-associated protein with death domain, Fas ligand, and TNF-related apoptosis-inducing ligand (TRAIL) dsRNA, polyI:C (4, 110) IAV (4, 5, 10, 115) Sendai virus (110) TRAIL Virus control by apoptosis induction in infected cells IAV (6, 170, 171) Tissue injury by apoptosis of both infected and non-infected alveolar epithelial cells, lung macrophages IAV (5, 7, 10) RSV (137) Necrosis of fibroblasts, dendritic cells, and epithelial cells IAV (146, 147, 168) Increased cellular infiltration CoV (175) Decreased expression of Na,K-ATPase, impaired epithelial fluid reabsorption IAV (11) iNTRODUCTiON In 1957, Isaacs and Lindenmann (1) first recognized the potential of a soluble and probably cell-derived factor to combat influenza virus infection and named this factor interferon [(IFN) from latin interferre, to interfere].
cord-344798-q34j4zxu	2020	title: Interferon gamma, TGF-β1 and RANTES expression in upper airway samples from SARS-CoV-2 infected patients The aim of this study was evaluate inflammatory response using the expression of immune mediators with antiviral, immunosuppression and chemotactic functions in the primary site of SARS-CoV-2 replication, at early stage of infection. J o u r n a l P r e -p r o o f Taking into account that Ct value has a correlation with the amount of RNA present in the samples, it was found that medians and IQR of SARS-CoV-2 viral titer was similar in asymptomatic (33.00, 29.00-37.00) and symptomatic (30, 27 .00-37.00) cases; and comparison between groups did not show difference (p=0.4373). As show our results, SARS-CoV-2 infection induced high IFN-γ expression in swabbed cells from upper airway; its expression was higher in symptomatic patients in comparison with asymptomatic individuals. Also, positive correlation between IFN-γ and TGF-β1 provided evidence of immune response control could determinate the asymptomatic presentation of SARS-CoV-2 infection.
cord-345854-f0dq94j1	2006	We examined whether polymorphisms of IFN-γ,TNF-α and IL-10 affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS). In this study, we hypothesized that the polymorphisms of the cytokine genes, i.e. IFN-γ +874A/T, TNF-α -308G/A, IL-10 -1082G/A and -592A/C, might be associated with SARS. We tested our hypotheses in 476 SARS patients and 449 healthy controls and found that polymorphism of IFN-γ +874A allele was associated with susceptibility to SARS in a dose-dependent manner. The frequencies of genotypes and alleles of the 4 single nucleotide polymorphisms (SNPs) were compared between the SARS patients and healthy controls by 3 × 2 and 2 × 2 chi square test respectively. Our case-control study genotyped the 4 SNPs IFN-γ +874A/T, TNF-α -308G/A, IL-10 -1082G/A and -592A/C in 476 Chinese patients with SARS and 449 healthy controls. Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection
cord-346212-mcnr7bcp	2020	
cord-346836-6jyv0q5e	2011	RVFV infection in humans usually causes a self-limiting, acute and febrile illness; however, a small number of cases progress to neurological disorders, partial or complete blindness, hemorrhagic fever, or thrombosis. This review describes the pathology of RVF in human patients and several animal models, and summarizes the role of viral virulence factors and host factors that affect RVFV pathogenesis. RVFV infection in humans primarily causes a self-limiting febrile illness; however, some patients develop hemorrhagic fever, neurological disorders, or blindness after the febrile period [5, 7, 8] . Inbred rat strains mimic the disparate human response to rift valley fever virus infection Clinical, virological and serological response of the west african dwarf sheep to experimental infection with different strains of rift valley fever virus
cord-347200-dtwhd6zy	2014	Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγ production against bacteria, fungi, viruses, and parasitic infections. Since NK precursors and other ILC populations in secondary lymphoid tissues express varying levels of this integrin, it may be possible that an NK-DC interaction is a requirement for immature NK cells to be signaled to home to mucosal sites. During mucosal infections of humans and mice, NK cells are recruited to sites of infection and play an important role in immune defense [6, 48] . Therefore the cytokine milieu present in the different mucosal tissues in addition to activating signals stimulated that by diverse pathogens help NK cells respond to infection. NK cells in humans are also important for innate control of gut mucosal infections. During infection, resident mucosal tissue NK cells respond primarily through IFN production, which contributes directly to early control of pathogens.
cord-347225-gh51ag2x	2020	INTERPRETATION: Aerosol inhalation of IFN-κ plus TFF2 is a safe treatment and is likely to significantly facilitate clinical improvement, including cough relief, CT imaging improvement, and viral RNA reversion, thereby achieves an early release from hospitalization. Therefore, to evaluate the efficacy and safety of intranasal inhalation of TFF2 and IFN-k protein for SARS-CoV-2 infection, we conducted an open-label, nonrandomized, clinical trial in adult patients hospitalized with moderate COVID-19 disease in China. In this trial, any AE from the beginning of aerosol inhalation to 5 days after the end of the last aerosol inhalation were taken as an adverse event during treatment (TEAE); The secondary objective of the pilot study was to evaluate the clinical efficacy of IFN-k plus TFF2 as compared to the control group as assessed by days of hospitalization staying, CT imaging improvement and cough relief time and negative reversion of viral RNA after 10 days of treatment.
cord-347298-7kqrl3rv	2010	Thus, it appears unlikely that a lack of APCs is a contributing factor in testicular immune privilege, although differences in the number and distribution of MHC class II-expressing cells in the interstitial tissue of different species or strains may help to explain differences in susceptibility to autoimmune orchitis (Flickinger et al. Moreover, while inhibition of Leydig cell steroidogenesis during inflammation may involve indirect effects at the level of the pituitary, or the actions of inflammatory mediators produced by the testicular macrophages and Sertoli cells, there is evidence that these cells can also respond directly to TLR ligands (Bhushan et al. Activation of p38/Jnk is implicated in the stimulation of proliferation by immature Sertoli cells and the regulation of blood-testis barrier dynamics, steroidogenesis, and multiple inflammatory responses, including the production of IL6, iNOS, monocyte chemoattractant protein 1, and leukocyte adhesion molecules, in the mature Sertoli cell (De Cesaris et al.
cord-347460-9vechh4x	2020	Three components are crucial for SARS-CoV induced diseases: 1) the role of CD8+ T cells in defense against the virus, which causes apoptosis in the infected cells, 2) interactions of the virus with macrophages and dendritic cells, which initiate the early innate and subsequent adaptive immune responses, and 3) type I interferon (IFN) system, an innate response against viral infections, which can inhibit virus replication in the early phase. Existing information suggests that the SARS-CoV-infected airways and alveolar epithelial cells secrete abundant chemokines to attract immune cell infiltrations to the lungs, including macrophages and neutrophils, thereby causing damage due to high levels of proinflammatory cytokines and other mediators secreted by these cell types. After a decade of research on coronavirus, unfortunately, still there are no licensed vaccines, effective specific antivirals, nor drug combinations supported by high-level evidence to treat the infection, especially for newly emerging strains such as SARS-COV-2 [59] .
cord-347946-i6kx3n6m	2016	Like sickness behavior, depression in response to immune activation aided in host defense both directly (ie, raised body temperature and energy conservation behaviors) and indirectly (social avoidance, energy conservation, and hypervigilance; Raison and Miller, pathogenhost defense theory of depression [PATHOS-D]) Adaptive explanations for associations between MDD and altered immune functioning are not considered (frequent unexamined assumption of researchers working on proximal mechanisms) Toll-like receptor (TLR) mRNA and protein have been reported to be elevated in both the periphery and CNS of individuals with MDD (Hung et al, 2014 (Hung et al, , 2015 Keri et al, 2014; van Dooren et al, 2016) , with some evidence suggesting that successful pharmaco-or psychotherapy reduces peripheral TLR activity (Keri et al, 2014; Hung et al, 2015) .
cord-348684-xbxwpmxq	2020	Interferon regulatory factors (IRFs) play pivotal and critical roles in innate and adaptive immune responses; thus, precise and stringent regulation of the stability and activation of IRFs in physiological processes is necessary. Knowledge of how these proteins function and interact with IRFs may provide a better understanding of the regulation of IRFs in immune responses or other biological processes and exciting targets for the development of drugs aimed at regulating the functions of specific E3 ligases or DUBs. Ubiquitination is a type of reversible cellular protein PTM. Furthermore, K63-linked polyubiquitination and monoubiquitination, the second most common type of ubiquitin linkage, mediate proteasome-independent effects, which play an important role in activating many components of different signaling pathways and participate in many biological processes (Ning et al., 2011) . c-Cbl, a member of the Cbl (Casitas B-lineage lymphoma) family, negatively regulates IRF3 protein stability by interacting with the C-terminal domain of IRF3 via its TKB (tyrosine kinase binding) domain and promotes K48-linked polyubiquitination-dependent proteasomal degradation of IRF3 (Zhao et al., 2016) .
cord-348993-8r4fhzlm	2013	CONCLUSIONS: The present work demonstrated that nasal administration of immunobiotics is able to beneficially modulate the immune response triggered by TLR3/RIG-I activation in the respiratory tract and to increase the resistance of mice to the challenge with RSV. Considering this background, the aims of this study were: a) to investigate whether the nasal administration of Lr05 or Lr06 are able to improve respiratory antiviral defenses and beneficially modulate the immune response triggered by TLR3/RIG-I activation; b) to evaluate whether viability of Lr05 or Lr05 is indispensable to modulate respiratory immunity considering that it was reported that heat-killed lactobacilli strains are able to improve lung defenses [11, 15, 16] and; c) to conclusively demonstrate the protective effect of Lr05 and Lr06 by evaluating their capacity to improve the resistance of infant mice against RSV challenge.
cord-349647-cfjrwt44	2019	However, the recognition that RV infection is associated with more severe clinical manifestations in people with chronic lung diseases such as asthma and COPD provided a new impetus to research and a new direction to human experimental infection studies. 166 These studies extend the use of RV infection in mice to new areas, including mechanisms of early life infection susceptibility, to mechanisms of secondary bacterial infection/compromised antimicrobial immunity and experimental exploration of clinical risk factors associated with increased likelihood to develop virus-induced exacerbations of respiratory diseases. 190 In the same elastase-induced model, fluticasone proprionate treatment reduced IFN responses, increased viral load, suppressed airway immune cell numbers (lymphocytes and neutrophils), suppressed inflammatory cytokines (IL-6, TNFα), and increased mucus production, following RV-A1 exacerbation. Human experimental RV challenge studies have shed light on the biology of RV infection and the mechanisms associated with RV-induced exacerbations of chronic respiratory diseases.
cord-351489-tzmev77c	2020	They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. In this primary screening, chloroquine, lopinavir, and remdesivir which were recently reported to have anti-SARS-CoV-2 activity, exhibited about 1.3-2.0 log10 copies/mL reduction in viral RNA load ( Figure 1 ). In comparison, recombinant IFN-β demonstrated the most potent anti-SARS-CoV-2 activity, with Avonex (IFN-β1a), Rebif (IFN-β1a), and Betaferon (IFN-β1b) each achieving about 3 log10 copies/mL reduction in viral load. In our primary screening using a fixed antiviral agent concentration and virus inoculum, we identified recombinant IFNs and lipogenesis modulators to be the most potent anti-SARS-CoV-2 agents among 22 broad-spectrum antivirals.
cord-351520-c5fi2uoh	2010	Recently, we and others identified a new adapter protein called mediator of IRF3 activation (MITA, also known as STING), which plays a critical role in virus-induced type I IFN expression (Ishikawa and Barber, 2008; Zhong et al., 2008) .
cord-351532-2yd4wg9v	2020	title: No Statistically Apparent Difference in Antiviral Effectiveness Observed Among Ribavirin Plus Interferon-Alpha, Lopinavir/Ritonavir Plus Interferon-Alpha, and Ribavirin Plus Lopinavir/Ritonavir Plus Interferon-Alpha in Patients With Mild to Moderate Coronavirus Disease 2019: Results of a Randomized, Open-Labeled Prospective Study The proportion of patients with SARS-CoV-2 nucleic acid negativity in the LPV/r+IFN-α-treated group (61.1%) was higher than the RBV+ IFN-α-treated group (51.5%) and the RBV+LPV/r+IFN-α-treated group (46.9%) at day 14; however, the difference between these groups was calculated to be statistically insignificant. The office of National Health Commission of the People''s Republic of China, and the National Administration Bureau of Traditional Chinese Medicine have jointly issued different versions of the "Guidelines for diagnosis and treatment of novel coronavirus pneumonia", in which LPV/r, IFNa, and RBV are recommended for on-trial use in patients with COVID-19.
cord-351845-bli3qm8w	2020	Towards this goal, in this study, we have generated a human-SARS-CoV-2 interactome based on recently published RNA-Seq analysis of human adenocarcinomic alveolar basal epithelial (A549) cells infected with SARS-CoV-2, and identified disease-related functional genes that will provide the insights into the patho-J o u r n a l P r e -p r o o f 4 mechanisms of COVID-19. Overall, the analysis demonstrated that the upregulated genes are mainly linked to the host response to SARS-CoV-2 infection, type I interferon signaling and the cytokine-mediated signaling pathway. The PPI network analysis indicates that the pathways are enriched in host response to virus infection, type I interferons signaling, and cytokine activation. [74] reported high SARS-CoV-2 loads very early during infection, suggesting that the virus may have developed arsenals that is able to delay the IFN response by inhibiting innate immune signaling.
cord-353062-c6luoo3m	2015	To address both tissue and subtype specificity in the interferon response, we treated primary human hepatocytes and airway epithelial cells with IFNα, IFNλ3 or IFNλ4 and assessed interferon mediated gene regulation using transcriptome sequencing. 23 In order to determine whether IFNλ4 can induce an alternative set of genes, that are not induced in the classical IFN response, we have compared the transcriptional response after IFNα, IFNλ3 and IFNλ4 stimulation in both primary human hepatocytes (PHH) and primary human airway epithelial (HAE) cells using transcriptome sequencing (RNA-seq). Compared with a recently published microarray analysis of type I and type III IFN responses in PHH, which used similar statistical thresholds but substantially higher IFNλ concentrations than our study (1000 ng ml − 1 ), 11 our RNA-seq data provide a more complete estimate of the IFN response (87 versus 50 genes significantly regulated by IFNλ3).
cord-353337-o302vxqm	2020	To study the effects of L pro on the induction of type I IFN in picornavirus-infected cells, we used two previously generated recombinant viruses; EMCV-L Zn , which contains inactivating mutations in the zinc-finger domain of the Leader (i.e. EMCV''s RLR signaling antagonist) [1, 43, 44] , and EMCV-L pro , which was derived from EMCV-L Zn and additionally encodes FMDV L pro at the N-terminus of its polyprotein ( Fig 1A) [45]. Cleavage of RLR signaling proteins by FMDV L pro correlates with type I IFN suppression degradation of NF-κB p65 and DUB activity as well as to impair L pro ''s ability to reduce IFN-β mRNA expression [36, 39] , also affected L pro ''s ability to cleave MAVS and TBK1. Notably, infection with EMCV L pro L143A, which displayed wt deISGylase/DUB activity but is strongly impaired in its ability to cleave/degrade RLR signaling proteins MAVS, TBK1 and NFκB p65, failed to suppress the induction of IFN-β mRNA.
cord-353826-owoec2ud	2020	Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Analysis of SARS-CoV-2 S proteinspecific murine splenocyte responses by IFN-γ ELISpot assay showed no statistically significant difference between the primeonly and prime-boost vaccination regimens, in either strain of mouse (Fig. 1a) . SARS-CoV-2 S protein-specific antibody responses following ChAdOx1 nCoV-19 prime-only and prime-boost vaccination regimens in mice and pigs SARS-CoV-2 S protein-specific antibody titres in serum were determined by ELISA using recombinant soluble trimeric S (FL-S) and receptor binding domain (RBD) proteins. Small animal models have variable success in predicting vaccine efficacy in larger animals but are an important To analyse SARS-CoV-2 S-specific T cell responses, all mice were sacrificed on day 49 for isolation of splenocytes and pigs were blood sampled longitudinally to isolate PBMC.
cord-353957-0pjg25kn	2017	Taken together, these results reveal that induced expression of avian IFITM1 and IFITM3 in response to ATMUV infection can effectively restrict the virus replication, and suggest that increasing IFITM proteins in host may be a useful strategy for control of ATMUV infection. Interestingly, we observed that ATMUV infection could trigger duck innate immune response including robust expression of particular type I and type III IFNs and IFITM family proteins. Our previous studies had shown that ATMUV infection effectively triggers the host innate immune response, including robust upregulation of type I and type III IFNs and some critical ISGs in chicken and CEF (Chen et al., 2016a) . To confirm these findings, DF-1 cell lines expressing specific shRNA targeting each of these IFITMs were infected with ATMUV and harvested at 36 hpi, followed by qRT-PCR assay to detect mRNA expression of viral genes.
cord-354000-jxqskt4k	2014	Here, we demonstrate that IFN-α or -β treatment of keratinocytes substantially decreases human papillomavirus 16 (HPV16) infection while robustly inducing IFITM1, 2 and 3 expression. IFITM protein expression induced by type I IFN inhibits infection of many RNA viruses [22] [23] [24] [25] [26] [27] [28] [29] [30] . Therefore, we analyzed induction of IFITM1, 2 and 3 expression by IFN-b treatment in human keratinocytes, the natural host cells for HPV. To determine the effect of IFITMs on HPV16 entry, HeLa cells stably expressing c-Myc-tagged IFITM1, 2 or 3 or with vector alone ( Fig. 2A-B) were infected with HPV16-LucF. Using various epithelial cell lines and primary keratinocytes expressing IFITMs, we show that HPV infection is surprisingly enhanced by IFITM1 and IFITM3 overexpression (Fig. 2) . Taken together, our results suggest that HPV and other DNA viruses may have evolved to avoid IFITM1, 2 and 3 restriction during entry into host cells.
cord-354620-xf6glr2h	2020	Our study provided practical methods for isolating and culturing duck primary cells, and our results will facilitate further investigations of organ tropism, innate immune responses, latent infection, and the effectiveness of antiviral drugs for treating DPV and potentially other aerial bird pathogens. In the present study, we isolated five types of duck primary cells [duck embryo fibroblasts (DEFs), neurons, astrocytes, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages] to identify appropriate cell models for DPV, using tropism infection and innate immunologic assays. Upon stimulation with DNA viruses, monocytes/macrophages exhibit higher levels of IFN-β, ISG, and inflammatory cytokine expression than DEFs, neurons, astrocytes, and PBMCs. To elucidate the mechanisms associated with the different responses of the five types of duck primary cells to DNA and RNA virus analogs, the basal levels of innate immune factors were compared.
cord-354730-hfau2odb	2014	PRRSV interplays with host IFN production and IFN-activated signaling, which may contribute to the delayed onset and low level of neutralizing antibodies, as well as weak cell-mediated immune response in infected pigs. This review summarizes the recent advances in the research of PRRSV interference with IFN-mediated innate immunity, the viral proteins involved, and their molecular mechanisms, as well as diverse effects by different strains and in different cell types. These transcription activation factors translocate into the nucleus and result in induction of type I IFNs and expression of inflammatory cytokines, which not only lead to an antiviral state of the neighboring uninfected cells, but also serve as key regulators to evoke adaptive immune response. Porcine reproductive and respiratory syndrome virus nonstructural protein 1 modulates host innate immune response by antagonizing IRF3 activation Porcine reproductive and respiratory syndrome virus inhibits type I interferon signaling by blocking STAT1/STAT2 nuclear translocation
cord-354762-3a3a3ku9	2020	title: SARS-CoV-2 (COVID-19): INTERFERON-EPSILON MAY BE RESPONSIBLE OF DECREASED MORTALITY IN FEMALES IFN is particularly expressed in epithelial cells and it is essential in skin and mucosal immunity (lung, intestines and reproductive tissues) of all African and Asian pangolin species (Choo and others, 2016) . IFN, like the other type I IFNs, might be responsible of decreased mortality in females because of its antiviral effects. The JAK/STAT pathway responds to type I IFN secreted from neighboring cells and SARS-CoV proteins have been shown to affect this pathway before (Frieman and Baric, 2008) . JAK-STAT signal blocking by baricitinib (a selective JAK1 and JAK2 inhibitor) produces an impairment of IFN-mediated antiviral response, with a potential facilitating effect on the evolution of SARS-CoV-2 infection. Interferon-epsilon protects the female reproductive tract from viral and bacterial infection
cord-355671-t890eixt	2020	FMDV Lpro is a papain-like protease (PLP) known to block the cellular innate immune response, at both the transcriptional and translational level by utilizing different mechanisms, including (i) shutting down translation of host capped mRNAs through the cleavage of the translation initiation factor eIF4G (5, 6); (ii) downregulating IFN mRNA expression by causing degradation of NF-B, IRF-3, IRF-7, and LGP2 (7-10); (iii) targeting the chromatin remodeling machinery to disrupt the expression of IFN and ISG mRNAs (11) ; and (iv) targeting of G3BP1/2 to block stress granule formation (12) . Importantly, engineering of an infectious clone carrying this mutation (LproW105A) rendered a viable FMDV with a perceptible level of attenuation and reduced deISGylation and DUB activity compared with wild-type (WT) virus during infection of porcine cells. To confirm these results using the FMDV host-specific ISGylation machinery during infection, we cloned the porcine ISG15 in a replicationdefective human adenovirus type 5 (Ad5) vector (Fig. 5B) and examined its antiviral activity in swine cells.
cord-355839-o0m71kvw	2019	ATF2, activating transcription factor 2; CDS, cytoplasmic DNA sensor; ER, endoplasmic reticulum; IFN, interferon; IKK, inhibitor of nuclear factor kappa-B kinase; IKKε, inhibitor of nuclear factor kappa-B kinase subunit epsilon; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MAVS, mitochondrial antiviral-signaling protein; MDA5, melanoma differentiation-associated protein 5; MyD88, myeloid differentiation primary response protein MyD88; NF-kB, nuclear factor-kappa B; NOD2, nucleotide-binding oligomerization domain-containing protein 2; PAMP, pathogenassociated molecular pattern; PRR, pattern recognition receptor; RIG, retinoic-acid-inducible gene-I; RLR, RIG-I-like receptor; RSV, respiratory syncytial virus; STING, stimulator of interferon protein; TBK1, tank binding kinase 1; TICAM1, toll/interleukin-1 receptor domain-containing adapter molecule 1; TIRAP, toll/ interleukin-1 receptor domain-containing adapter protein; TLR, toll-like receptor; TRAF3, tumor necrosis factor receptor-associated factor 3; TRAF6, tumor necrosis factor receptor-associated factor 6; TRAM, toll-like receptor adaptor molecule.
cord-356094-sbtigcfr	2019	perforatum was ethyl acetate extraction section (HPE), and results showed that treatment with HPE significantly reduced the relative messenger ribonucleic acid (mRNA) expression and virus titer of IBV, and reduced positive green immunofluorescence signal of IBV in chicken embryo kidney (CEK) cells. The results of adaptation and replication in CEK cells, such as CPE, reverse transcription polymerase chain reaction (RT-PCR), and IBV growth curve determined by tissue culture infective dose (TCID 50 ) at different time were tested. The relative mRNA expression level of IBV-N gene was detected by qRT-PCR and the virus titer of IBV was determined by TCID 50 to analyze the antiviral effect of HPE, HPW and SEE (Figure 3) . FIgUre 8 | The effects of Hypericum perforatum ethyl acetate (HPE) on infectious bronchitis virus (IBV) messenger ribonucleic acid (mRNA) expression levels of trachea (A) and kidney (B).
cord-356197-js7l86fh	2011	Microarray analysis revealed that HP-PRRSV infection has affected PAMs in expression of the important genes involved in cytoskeleton and exocytosis organization, protein degradation and folding, intracellular calcium and zinc homeostasis. Genome-wide transcriptional responses of lungs of Landrace×Yorkshire crossbred piglets to a classical North American type PRRSV strain infection was analyzed by Solexa/Illumina''s Digital Gene Expression (DGE) System, which is a tag-based high-throughput transcriptome sequencing method [6] . This systematic analysis of the pulmonary gene expression profiles suggested that upregulation expression of pro-inflammatory cytokines, chemokines, adhesion molecules and inflammatory enzymes and inflammatory cells, antibodies, complement activation were likely to result in the development of inflammatory responses during PRRSV infection processes [6] . Microarray analysis revealed that HP-PRRSV infection has affected PAMs in vivo in expression of the important genes involved in cytoskeleton and exocytosis organization, protein degradation and folding, intracellular calcium and zinc homeostasis.