key: cord-0790182-qwgxm1ol authors: Li, Geng; Fan, Yaohua; Lai, Yanni; Han, Tiantian; Li, Zonghui; Zhou, Peiwen; Pan, Pan; Wang, Wenbiao; Hu, Dingwen; Liu, Xiaohong; Zhang, Qiwei; Wu, Jianguo title: Coronavirus infections and immune responses date: 2020-02-07 journal: J Med Virol DOI: 10.1002/jmv.25685 sha: 3cfc7674f189b49a38eacfb52d12f6e3d5d36f98 doc_id: 790182 cord_uid: qwgxm1ol Coronaviruses (CoVs) are by far the largest group of known positive‐sense RNA viruses having an extensive range of natural hosts. In the past few decades, newly evolved Coronaviruses have posed a global threat to public health. The immune response is essential to control and eliminate CoV infections, however, maladjusted immune responses may result in immunopathology and impaired pulmonary gas exchange. Gaining a deeper understanding of the interaction between Coronaviruses and the innate immune systems of the hosts may shed light on the development and persistence of inflammation in the lungs and hopefully can reduce the risk of lung inflammation caused by CoVs. In this review, we provide an update on CoV infections and relevant diseases, particularly the host defense against CoV‐induced inflammation of lung tissue, as well as the role of the innate immune system in the pathogenesis and clinical treatment. The host innate immune system detects viral infections by using pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs). At present, the known PRRs mainly include toll-like receptor (TLR), RIG-I-like receptor (RLR), NOD-like receptor (NLR), C-type lectin-like receptors (CLmin), and free-molecule receptors in the cytoplasm, such as cGAS, IFI16, STING, DAI, and so on. PAMPs recognized by Toll-like receptors (TLRs) include lipids, lipoproteins, proteins, and nucleic acids of the bacterial, viral, parasite, and fungal origins. 6 The recognition of PAMPs by TLRs also occurs in cell membranes, endosomes, lysosomes, and endocytolysosomes and other locations in cells. 6 Different TLRs can induce different biological responses via subsequent activation of varied adapter proteins, such as MyD88, TIRAP, TRIP, and TRAM, but these adapter proteins all share the Toll/Interleukin-1 receptor (TIR) structure. 7 MyD88 is the first identified TIR family member, which acts as an adapter protein by almost all TLRs except TLR3. It mainly activates the transcription factors NF-kB and mitogen-activated protein kinases (MAPKs) pathways to induce inflammatory factors' expression. 6 Unlike MyD88, TRIF is an adapter protein of TLR3 and TLR4, which activates the transcription factors IRF3 and NF-kB to induce the expression of type I interferon and immuneinflammatory factors. The function of TRAM and TIRAP is to recruit TRIF molecules to the TLR4 receptor and MyD88 to the TLR2 and TLR4 receptors. Therefore, the TLR signaling pathways are classified as the MyD88-dependent pathway, which functions to activate immuneinflammatory factors, and the TRIF-dependent pathway, which functions to activate the type I interferons and inflammatory factors. 6 After a TLR is activated by the corresponding PAMP, MyD88 recruits the busy-1 F I G U R E 1 Coronavirus particle. Coronaviruses are enveloped, nonsegmented, positive-sense single-stranded RNA virus genomes in the size ranging from 26 to 32 kilobases. The virion has a nucleocapsid composed of genomic RNA and phosphorylated nucleocapsid (N) protein, which is buried inside phospholipid bilayers and covered by the spike glycoprotein trimmer (S). The membrane (M) protein (a type III transmembrane glycoprotein) and the envelope (E) protein are located among the S proteins in the virus envelope receptor-related kinases IRAK4, IRAKI, IRAK2, and IRAK-M. IRAK4 plays an important role in activating NF-kB and MAPKs downstream of MyD88. IRAK interacts with TRAF6, which causes its K-63 ubiquitination, and facilitates NEMO ubiquitination to activate NF-kB. TRIFdependent pathways activate IRF3 and NF-kB. 8, 9 In addition to activating NF-kB, TRIF-dependent pathways, they also activate IRF3 and interferon-β. 10 This process leads to T cell activation and differentiation, including the production of cytokines associated with the different T cell subsets (ie, Th17), followed by a massive release of cytokines for immune response amplification. The continued production of these mediators due to viral persistence has a negative effect on NK, and CD8 T cell activation. However, CD8 T cells produce very effective mediators to clear CoV. B, Attachment of CoV to DPP4R on the host cell through S protein leads to the appearance of genomic RNA in the cytoplasm. An immune response to dsRNA can be partially generated during CoV replication. TLR-3 sensitized by dsRNA and cascades of signaling pathways (IRFs and NF-κB activation, respectively) are activated to produce type I IFNs and proinflammatory cytokines. The production of type I IFNs is important to enhance the release of antiviral proteins for the protection of uninfected cells. Sometimes, accessory proteins of CoV can interfere with TLR-3 signaling and bind the dsRNA of CoV during replication to prevent TLR-3 activation and evade the immune response. TLR-4 might recognize S protein and lead to the activation of proinflammatory cytokines through the MyD88-dependent signaling pathway. Virus-cell interactions lead to the strong production of immune mediators. The secretion of large quantities of chemokines and cytokines (IL-1, IL-6, IL-8, IL-21, TNF-β, and MCP-1) is promoted in infected cells in response to CoV infection. These chemokines and cytokines, in turn, recruit lymphocytes and leukocytes to the site of infection. Red lines refer to inhibitory effects. Green lines refer to activating effects nucleocapsid proteins containing triphosphine RNA at the 5′-end can be recognized by RIG-I. 17 The double-stranded RNA with doublebasic acid at the 5′-end can be recognized by RIG-I. 18 When the viral 5′-terminal triphosphate end is recognized by the CTD structure, the ATP-dependent conformational change brings the CTD structure to form a complex with the double-stranded RNA, and the CARD structure is then released from its self-inhibition and interacts with MAVS. 19 MDA5 recognizes RNAs of picornaviruses, including poliovirus (PV) and Encephalomyocarditis virus (EMCV). MDAS-recognized RNA is characterized by long double-stranded RNA more than 1 kbp. Crystal structure analysis shows that the helicase and CTD structure of MDA5 are also surrounded by double-stranded RNA, the same as RIG-I. However, the CTD structure of MDA5 does not have a hat structure, 20 and the hat structure is necessary to have a triphosphate RNA interaction at the 5′-end. The CTD structure of MDA5 directly interacts with the double-stranded RNA, so that the 5′-end RNA can be freely released. 21 Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are a class of pattern recognition receptors, 22 which recognize components of pathogens and contain a conserved NOD structure. 23 NLR receptor family members are divided into three subclasses according to their functions. The first NLR subclass forms complexes with a variety of proteins and these complexes are defined as inflammasome that contains at least eight NLR proteins, including NLRP1, NLRP3, NLRP6, NLRC4, NLRC5W, and AY2. [24] [25] [26] The second subclass is essential to reproduction and embryo regeneration. 27 The third subclass is comprised of regulatory NLRs. These NLRs are positive or negative conditioned inflammatory signaling cascade pathways. When a virus invades the host, PRRs initially recognize the viral nucleic acid, collect the specific signal adapter protein, activate IRF3 and IRF7 before being translocated to the nucleus and promote the synthesis of type I interferons (IFNs). Type I IFNs subsequently activate the downstream JAK-STAT signal pathway, promote the expression of IFN-stimulated genes (ISGs). 37, 38 As the host's major antiviral molecules, IFNs limit virus spread, and play an immunomodulatory role to promote macrophage pha- RIG-I/NF-κB-dependent pathway 45 and the disorder of the JAK-STAT signaling pathway directly affects the spread of virus. 46 Although SARS-CoV and other coronaviruses are sensitive to IFN-a/b, these viruses remain highly pathogenic. Reportedly, the N protein of SARS-CoV acts as an antagonist of immune escape protein and host interferon response. [47] [48] [49] It is reported that EV71 infection downregulates JAK1, p-JAK1, and p-TYK2, inhibits p-STAT1/2, and blocks the JAK-STAT signaling pathway mediated by type I IFNs, thereby hindering the function of IFNs and promoting EV71 replication and proliferation in host cells. 50 Ebola virus (EBOV) promotes cytokine signal inhibitory factor-1 (SOCS1) and blocks the JAK-STAT signal pathway by directly binding to phosphorylated JAK, resulting in the inhibition of JAK activation. 51 In addition, influenza A virus can inhibit the IFN-I downstream pathway by inducing the expression of SOCS3. 52 Defensins are a family of endogenous antibiotic peptide molecules, which widely exist in human, animals, and plants, and are important for the host's innate defense system. Defensins have broad-spectrum antimicrobial activities. In vitro inhibition experiments show that defensins have killing effects on bacteria, fungi, mycoplasma, chlamydia, spirochetes, tumor cells, and viruses. 60, 61 Defensins of human and rabbit neutrophils are mainly found in the eosinophilic granules of neutrophils. They are small molecular cationic polypeptides composed of 29 to 34 amino acid residues, with a relative molecular weight of 3500 to 4000 dolt and three intramolecular disulfide bonds. They are main components of the neutrophils independent of oxygen sterilization. 62, 63 Human α-defensin HNP-1 inactivates herpes simplex virus type I and type II (HSV-1 and HSV-2), cytomegalovirus (CMV), VSV, and IAV. 64, 65 Purified defensins of guinea pigs, rabbits, and rats have weak anti-HIV-1 activity. 66, 67 However, some studies showed that purified human neutrophil defensin (HNP1-3) and rabbit neutrophil defensins (RNP1-5) could neither inhibit nor kill SARS-CoV. 68 The reappearance of SARS-CoV is still a noteworthy problem. B cell subsets with phenotypes characteristic of naive, non-isotype- CoVs. 85 The antigen stimulation of MERS-CoV infection was clarified by using the specific 9-mer peptide "CYSSLILDY", which located at position 437 to 445 within the region of the S glycoprotein. 85 The sequence has the highest B cell antigenicity plot and has the ability to form the greatest number of interactions with MHCI alleles in a computerized simulation. 86 Reports show that humoral immunity is essential to control the persistent phase of CoV infection. More antibodies isolated from patients who have survived MERS-CoV infection have been described, including MCA1, CDC-C2, CSC-C5, CDC-A2, CDC-A10, MERS-GD27, and MERS-GD33. [87] [88] [89] The complement system plays a vital role in the host immune response to CoV infection. Primitively identified as a host-sensitive and nonspecific complement to adaptive immune pathways, the complement system provides a way for the innate immune system to detect and respond to foreign antigens. 90 Given its potential to damage the host tissues, the complement system is tightly controlled by inhibiting proteins in the serum. Virus encoded proteins help them evade the detection of the complement system, suggesting that complements are vital to the antiviral response. C3a and C5a have potent proinflammatory properties and can trigger inflammatory cell recruitment and neutrophil activation. C3a and C5a blockade acts as a treatment for acute lung injury, and anti-C5a antibody shows to protect mice from infection with MERS-CoV. 91 SARA-CoV infection activates the complement pathway and complement signaling contributes to disease. 92 The antibody response in vivo is a dynamic and complex mixture of monoclonal antibodies (mAbs), which work together to target different antigenic domains on the envelope glycoprotein of the virus. It is important to determine whether the antibodies are powerful in the adaptive immune responses to MERS-CoV infection. Research from all over the world have described more than 20 kinds of monoclonal antibodies, most of which are human or humanized antibodies. The virus uses its spike proteins as an adhesion factor to facilitate host entry through a special receptor called dipeptidyl peptidase-4 (DPP4). This receptor is considered a key factor in the signal transmission and activation of acquired and innate immune responses in infected patients. Thus, compared with the time-consuming vaccine preparation, the design of monoclonal antibodies against these proteins has a better protective effect. Human monoclonal antibody (m336) isolated from the phage display library interacts with the receptor-binding region of MES coronavirus spike protein and displays strong neutralization activity to MES-CoV in vitro. 93 Human monoclonal antibody m336 shows high neutralization activity to MERS-CoV in vitro. m336 reduces the RNA titer of lung by 40 000 to 90 000 folds. 94 After infection with MERS-CoV, monkeys were treated with high-titer hyperimmune plasma or monoclonal antibody m336. Both groups had relieved symptoms of clinical diseases, but the reduction of respiratory viral load was only found in the hyperimmune plasma group. Although both super immune plasma and m336 therapy show to mitigate the disease of the common marmoset, neither has the ability to prevent the disease completely. 95 Yet, HMab m336 is found to significantly reduce the viral RNA titers and viral-associated pathological changes in rabbit lung tissue. 94 Mice inoculated with S nanoparticles produced high-level neutralizing antibodies against homologous viruses, and these antibodies have no cross-protection with heteroviruses. 96 After being stimulated by SARS-CoV, immunized ferrets produced more rapid and stronger neutralizing antibody reaction than the control animals; however, the strong inflammatory reaction is observed in liver tissue. All this suggests that the expression of SARS-CoV S protein is associated with enhanced hepatitis. 97 On the other hand, the time course of SARS-CoV viremia and antibody response has been studied. 98 Laboratory testing of human suspected cases of novel coronavirus (nCoV) infection Novel Coronavirus (2019-nCoV) situation report-2 Middle East respiratory syndrome coronavirus (MERS-CoV) World Health Organization. WHO MERS global summary and assessment of risk Lessons from the past: perspectives on severe acute respiratory syndrome Pathogen recognition and innate immunity The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIFdependent Toll-like receptors Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses Regulation and function of IKK and IKK-related kinases Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6 RIG-I in RNA virus recognition RNA recognition and signal transduction by RIG-I-like receptors Viral RNA detection by RIG-I-like receptors Recognition of viral nucleic acids in innate immunity Pattern recognition receptors and inflammation Incoming RNA virus nucleocapsids containing a 5′-triphosphorylated genome activate RIG-I and antiviral signaling Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates The RIG-I ATPase domain structure reveals insights into ATP-dependent antiviral signalling Solution structures of cytosolic RNA sensor MDA5 and LGP2 C-terminal domains: identification of the RNA recognition loop in RIG-I-like receptors Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5 NOD-LRR proteins: role in host-microbial interactions and inflammatory disease The NOD: a signaling module that regulates apoptosis and host defense against pathogens NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity Cutting edge: NLRC5-dependent activation of the inflammasome AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC NOD-like receptors interfacing the immune and reproductive systems Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins Signalling through C-type lectin receptors: shaping immune responses Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of specklike aggregates and inflammasome activity Syk kinase-coupled C-type lectin receptors engage protein kinase C-sigma to elicit Card9 adaptor -mediated innate immunity A Toll-like receptor recognizes bacterial DNA RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway Cyclic GMP-AMP synthase is the cytosolic sensor of plasmodium falciparum genomic DNA and activates type I IFN in malaria Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion Mechanisms of innate immune evasion in reemerging RNA viruses. Current opinion in virology Viral innate immune evasion and the pathogenesis of emerging RNA virus infections Regulation of type I interferon responses P200 family protein IFI204 negatively regulates type I interferon responses by targeting IRF7 in nucleus Pattern recognition receptors: doubling up for the innate immune response Sensors of the innate immune system: their mode of action A novel method for autophagy detection in primary cells: impaired levels of macroautophagy in immunosenescent T cells In vitro screening platforms for identifying autophagy modulators in mammalian cells MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2 Interferon-stimulated genes: a complex web of host defenses Inhibition of beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3 Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists SARS-CoV nucleocapsid protein antagonizes IFN-beta response by targeting initial step of IFN-beta induction pathway, and its C-terminal region is critical for the antagonism Enterovirus 71 inhibits cellular type I interferon signaling by downregulating JAK1 protein expression Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1 Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression Dendritic cells as key players in systemic lupus erythematosus Development of dendritic cell system Exposure to nicotine adversely affects the dendritic cell system and compromises host response to vaccination Intracellular overexpression of HIV-1 Nef impairs differentiation and maturation of monocytic precursors towards dendritic cells HCV core and NS3 proteins manipulate human bloodderived dendritic cell development and promote Th 17 differentiation The effect of human immunodeficiency virus-1 on monocyte-derived dendritic cell maturation and function HIV-1-induced impairment of dendritic cell cross talk with gammadelta T lymphocytes Impact of neutrophils on antiviral activity of human bronchoalveolar lavage fluid Antibacterial activity of chemotherapeutic drugs against Escherichia coli and Staphylococcus pseudintermedius Application of antimicrobial peptides of the innate immune system in combination with conventional antibiotics-A novel way to combat antibiotic resistance? Defensins: antimicrobial and cytotoxic peptides of mammalian cells Phosphorylation of MAVS/VISA by Nemolike kinase (NLK) for degradation regulates the antiviral innate immune response Direct inactivation of viruses by human granulocyte defensins Defensins inhibit HIV replication in vitro Identification of innate immune antiretroviral factors during in vivo and in vitro exposure to HIV-1. Microb Infect Prior immunization with severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) nucleocapsid protein causes severe pneumonia in mice infected with SARS-CoV Genetic variation of the human alpha-2-Heremans-Schmid glycoprotein (AHSG) gene associated with the risk of SARS-CoV infection Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection Experimental adaptive evolution of simian immunodeficiency virus sivcpz to pandemic human immunodeficiency virus type 1 by using a humanized mouse model Regulatory T cells in arterivirus and coronavirus infections: do they protect against disease or enhance it? Viruses Rapid generation of a mouse model for Middle East respiratory syndrome Pre-and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection Virusspecific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection A tale of two cytokines: IL-17 and IL-22 in asthma and infection. Expert review of respiratory medicine Th17 Cells and the IL-23/IL-17 axis in the pathogenesis of periodontitis and immune-mediated inflammatory diseases T helper 17 cells as pathogenic drivers of periodontitis Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors Middle East respiratory syndrome coronavirus (MERS-CoV): infection, immunological response, and vaccine development Recombinant adenoviral vaccine encoding the spike 1 subunit of the Middle East Respiratory Syndrome Coronavirus elicits strong humoral and cellular immune responses in mice Computer aided prediction and identification of potential epitopes in the receptor binding domain (RBD) of spike (S) glycoprotein of MERS-CoV Ultrapotent human neutralizing antibody repertoires against Middle East Respiratory syndrome coronavirus from a recovered patient Human neutralizing monoclonal antibody inhibition of Middle East Respiratory Syndrome coronavirus replication in the common marmoset A novel human mAb (MERS-GD27) provides prophylactic and postexposure efficacy in MERS-CoV susceptible mice Different mechanisms of serum complement activation in the plasma of common (Chelydra serpentina) and alligator (Macrochelys temminckii) snapping turtles Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. mBio Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies Prophylaxis with a Middle East Respiratory Syndrome Coronavirus (MERS-CoV)-specific human monoclonal antibody protects rabbits from MERS-CoV Infection Efficacy of antibody-based therapies against Middle East respiratory syndrome coronavirus (MERS-CoV) in common marmosets Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice Immunization with modified vaccinia virus Ankara-based recombinant vaccine against severe acute respiratory syndrome is associated with enhanced hepatitis in ferrets Antibody response and viraemia during the course of severe acute respiratory syndrome (SARS)-associated coronavirus infection Coronavirus infections and immune responses The authors declare that there are no conflict of interests.