key: cord-0910294-cfnoxhtd authors: Zheng, Jian; Perlman, Stanley title: Immune responses in influenza A virus and human coronavirus infections: An ongoing battle between the virus and host date: 2018-02-01 journal: Current Opinion in Virology DOI: 10.1016/j.coviro.2017.11.002 sha: e6fb49fc69fd07b9a8233feb2d335b4c02721015 doc_id: 910294 cord_uid: cfnoxhtd Respiratory viruses, especially influenza A viruses and coronaviruses such as MERS-CoV, represent continuing global threats to human health. Despite significant advances, much needs to be learned. Recent studies in virology and immunology have improved our understanding of the role of the immune system in protection and in the pathogenesis of these infections and of co-evolution of viruses and their hosts. These findings, together with sophisticated molecular structure analyses, omics tools and computer-based models, have helped delineate the interaction between respiratory viruses and the host immune system, which will facilitate the development of novel treatment strategies and vaccines with enhanced efficacy. Jian Zheng and Stanley Perlman Respiratory viruses, especially influenza A viruses and coronaviruses such as MERS-CoV, represent continuing global threats to human health. Despite significant advances, much needs to be learned. Recent studies in virology and immunology have improved our understanding of the role of the immune system in protection and in the pathogenesis of these infections and of co-evolution of viruses and their hosts. These findings, together with sophisticated molecular structure analyses, omics tools and computer-based models, have helped delineate the interaction between respiratory viruses and the host immune system, which will facilitate the development of novel treatment strategies and vaccines with enhanced efficacy. Immune response: protective or pathogenic? The host immune system is composed of multiple tissues, cells and molecules and can protect hosts from infectious diseases by recognizing and eliminating pathogens efficiently. In one example, our studies of mice infected with SARS-CoV showed that the severity of SARS correlated with the ability to develop a virus-specific immune response, while inhibitory alveolar macrophages and inefficient activation of dendritic cells (DCs) delayed this process and aggravated disease [1] . In another study, Channappanavar et al. further demonstrated that dysregulated type I interferon (IFN) and inflammatory monocytemacrophage responses led to lethal pneumonia in SARS-CoV-infected mice [2] . In support of these data, inhibition of nuclear factor-kappaB (NF-kB)-mediated inflammation in SARS-CoV-infected mice increased survival [3] . Similar to their pathological roles in coronavirus infections, inappropriate or dysfunctional immune responses such as overactivation of NACHT, LRR and PYD domains-containing protein 3 (NLRP3), high-mobility group box 1 protein (HMGB-1) and interleukin-1beta (IL-1b), have been implicated in host tissue destruction [4-8] and persistent pathological changes in IAV-infected hosts [9] . Expression of the complex of tumor necrosis factor (TNF) superfamily 10 (TNFSF10), histone deacetylase 4 (HDAC4) and HDAC5 negatively correlated with the levels of TNFa, NF-kB and cyclooxygenase 2 (COX-2) and increases in their expression was correlated with improved prognosis of IAV-infected hosts [10] . In addition to their cell-intrinsic properties, lung macrophage and monocyte heterogeneity in localization in IAV infections also contributed to differences in outcomes [11] . of vaccinated IAV individuals or mice, in which hemagglutinin (HA), neuraminidase (NA) and glycosylation pattern mutations [24] , might hinder an effective antibody and T cell response. The contribution of innate immunity to immune defense is not limited in direct anti-viral effects [34] . Innate immune signals such as IFN-I not only interact with other innate immune elements such as monocytes and type-II IFN to limit IAVcaused tissue inflammation [35] , but also directly modulated the adaptive immune response. Both IFN-I and toll-like receptor 7 (TLR7) were also found to shape B cell-mediated immune responses against IAV [36], while RIG-I signaling was critical for efficient polyfunctional T cell responses [37] . Moreover, the increased mortality of IAV-infected mice in the absence of mitochondrial antiviral signaling (Mavs) and TLR7 was found to independent of viral load or myeloid differentiation primary response 88 (MYD88)-dependent signaling but dependent on secondary bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage [38 ]. As for innate immune cells, a population of lung-resident innate lymphoid cells (ILCs) in mice and humans that expressed CD90, CD25, CD127 and ST2 was found to contribute to airway epithelial integrity and its depletion resulted in diminished lung function and impaired airway remodeling [ Broadly neutralizing antibodies generally target conserved functional regions on HA. [21] Binding of antibody to an epitope masks the epitope and prevents the stimulation and proliferation of specific B cells. [30] MERS-CoV Recombinant receptor-binding domains of multiple MERS-CoVs induce cross-neutralizing antibodies against divergent human and camel MERS-CoVs. [28] T cell response IAV Vaccine-generated lung-resident memory CD8 T cells provide heterosubtypic protection to IAV infection. [31] Potential challenges in translating protective memory CD4 T cell responses in experimental animal models to patients. [19] MERS-CoV MERS-CoV efficiently infects human primary T cells and induces apoptosis. [14] SARS-CoV Memory T cell responses targeting the SARS coronavirus persist for up to 11 years postinfection. [23] Crosstalk between immune components IAV Cooperativity between CD8+ T cells, non-neutralizing antibodies, and alveolar macrophages is important for heterosubtypic IAV immunity. [20] Antibody specificity plays an important role in the regulation of ADCC. Cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions. [17] IgE cross-linking impairs monocyte antiviral responses and inhibits IAVdriven Th1 differentiation. [27] MERS-CoV Recovery from the Middle East respiratory syndrome is associated with antibody and T-cell responses. [32] Maintenance of immune memory IAV Levels of neutralizing antibodies against previously encountered IAV strains ('original antigenic sin') increase over time. [22] Low levels of circulating CD8+ T effector and central memory cells are associated with IAV infection severity upon re-challenge. [16] Regimen of a CTL-based vaccine/vaccine-component benefits from periodic boosting to prevent clinically evident IAV infection. [26] Multifunctional CD4+ T-cell responses were maintained only in patients with recurrent infections. [29] Immunopathology IAV IAV-specific CD8+ T cells exacerbate infection following high dose challenge of aged mice. [25] Different subsets of CD8+ T cells interact with subsets of innate cells through costimulatory molecules to balance protection and immunopathology. [15] Identification of protective and pathogenic T cell epitopes in IAV H7N9infected patients. [18] Immunotherapy IAV, CoV High titer anti-IAV or CoV sera may be useful prophylactically and therapeutically in exposed and infected patients. With the increasing accumulation of knowledge of molecular interactions between host cells and viruses, additional host molecules and normal biological processes [51-65,66 ,67-69] were found to participate in the viral replication cycle (summarized in Table 2 ). To clarify the roles of these molecules and processes in virus infection, host genetic determinant screening [70] [71] [72] , immunomics and Public Health Omics [73] , host lipid omics [74 ] and characterization of the epigenetic landscape [75] were used to supplement conventional analyses. Moreover, information about interaction between immune and parenchymal cells also facilitated efforts to optimize antiviral response while reducing unwanted side effects [76 ,77 ] . Computer modeling of host-pathogen interactions is likely to be used more in the future, as additional parameters are identified. Thus, computer modeling helped in prediction of clinical outcomes, demonstrating key roles for the innate immune response and the interval between infections [78] . These novel methodologies are likely to provide additional approaches to identifying targets for novel antiviral therapies. The IAV non-structural protein NS1, perhaps the bestcharacterized viral immunoevasive protein, binds doublestranded RNA (dsRNA) to inhibit host innate immune responses [79] [80] [81] . Recently, NS1 was also found to bind cellular dsDNA and prevent the loading of transcriptional machinery onto the DNA, thus attenuating expression of antiviral genes [82] . Meanwhile, the C-terminal domain of NS1 blocked IFN-beta production by targeting TNF receptor-associated factor 3 (TRAF-3) [83] , while other domains of the protein inhibited interferon regulatory transcription factor 3 (IRF3) [84] and RNA-dependent protein kinase (PKR) activation [85] . Another IAV protein, neuraminidase (NA), was shown to remove sialic Immune responses in respiratory virus infections Zheng and Perlman 45 Table 2 Recent findings related to intrinsic molecules and biological processes involved in IAV and CoV infectionss. Ref. Cell cycling proteins IAV Competitive inhibition of IAV M1-M2 interaction by cyclin D3 impairs infectious virus packaging, resulting in attenuation Apoptosis-related signals IAV Apoptosis signaling modulates IAV propagation, innate host defense, and lung injury. [60] Sex hormones-related signals IAV Progesterone-based contraceptives reduce adaptive immune responses and protection against subsequent IAV infections. [59] Male mice were more susceptible to SARS-CoV infection compared with agematched females, while estrogen receptor signaling played a critical role in protecting females from SARS-CoV-mediated pathogenesis. [53] CHD chromatin remodeler IAV CHD1 is a proviral regulator of IAV multiplication. [63] Nuclear import and export machinery IAV IAV have evolved different mechanisms to utilize importin-alpha isoforms, affecting importation on both sides of the nuclear envelope. [65] Activation of the interferon induction cascade by IAV requires viral RNA synthesis and nuclear export. [61] Human heat shock protein 40 promotes IAV replication by assisting in the nuclear import of viral ribonucleoproteins. [52] Preferential usage of importin-alpha7 isoforms by seasonal IAV in the human upper respiratory tract makes it a target of selective pressure. [64] Vesicular trafficking IAV IAV infection modulates vesicular trafficking and induces Golgi complex disruption. [68] IAV enhances its propagation through modulating Annexin-A1 dependent endosomal trafficking. [51] IAV ribonucleoproteins modulate host recycling by competing with Rab11 effectors. [67] SARS-CoV A predicted beta-hairpin structural motif in the cytoplasmic tail of the SARS-CoV E protein is sufficient for Golgi complex localization of a reporter protein and functions as a Golgi complex-targeting signal. [54] MERS-CoV CD9-facilitated condensation of receptors and proteases allows MERS-CoV pseudoviruses to enter cells rapidly and efficiently. [56] Exosome secretion IAV Exosome deficiency uncoupled chromatin targeting of the viral polymerase complex and the formation of cellular-viral RNA hybrids, which are essential RNA intermediates that license transcription of antisense genomic viral RNAs Autophagy IAV Autophagy induction regulates IAV replication in a time-dependent manner. [58] SARS-CoV CoV nsp6 restricts autophagosome expansion. [55] Cellular senescence IAV Cellular senescence enhances viral replication. [62] Coagulation IAV Beneficial effects of inflammation-coagulation interactions during IAV infection [69] acid residues from NKp46, resulting in reduced recognition of HA and enhancing immune evasion of NK cells [86] . In addition, the IAV M2 protein was shown to reverse bone marrow stromal antigen 2 (BST-2)-mediated restriction of virus release via proteasomal pathways [87] . To evade the host immune system, IAV also inhibits host but not viral mRNA nuclear export [88] , without impairing nuclear viral ribonucleoprotein (vRNP) import [89] . In addition, productive viral replication in macrophages resulted in decreased phagocytosis via downregulation of Fc receptors CD16 and CD32, potentially playing a role in IAV pathogenesis [90] . The crucial role of the IFN response makes it a preferred target for viral evasion. Besides NS1, multiple virusencoded molecules including the nucleoprotein [64], the fusion peptide of HA2 (HA2-FP), HA1 and some variants of polymerase subunits PB1-F2, PB1, PB2, PA all counteract the interferon response [91] . Interestingly, some host cellular molecules are also utilized by IAV to block IFN expression. Using RNA interference, knockdown of a host factor, the double PHD fingers 2 gene (DPF2) [92] , resulted in decreased expression of IAV proteins, by releasing IFN-b production from DPF2-mediated suppression [92] . The CoV endonuclease, nsp15, efficiently prevented activation of host cell dsRNA sensors including melanoma differentiation-associated protein 5 (Mda5), 2 0 -5 0 oligoadenylate synthetase (OAS) and PKR [93, 94 ] , while coronavirus-encoded proteases countered innate immunity, including the IFN response, through diverse pathways [95] . A recent investigation further showed that SARS-CoV nucleocapsid inhibited Type I interferon production by interfering with tripartite motif protein 25 (TRIM25)-mediated RIG-I ubiquitination [96] . Recent studies of cellular metabolic processes [97, 98] and post-transcriptional protein modification [99, 100] identified additional approaches used by viruses to evade host immune responses [101] , and to facilitate optimal replication [102] . For example, IAV delayed apoptosis of infected cells by activating a signal transducer and activator of transcription 3 (stat-3)-related pathway, allowing prolonged replication [103] . Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), critical for expression of reactive oxygen species (ROS), is often activated in endocytic compartments by RNA and DNA viruses, exacerbating virus-mediated pathogenicity [104 ] . In addition to important roles for host proteins [105] , the role of lipids [74 ] in respiratory virus infections has also drawn increasing attention. Zhao et al. reported that agerelated increases in prostaglandin D2 (PGD 2 ) expression in mouse lungs correlated with a progressive impairment in DC migration to DLNs, causing diminished T cell responses upon IAV or SARS-CoV infection [106] . In a subsequent study, Vijay et al. demonstrated a critical role for phospholipase A2 group IID (PLA 2 G2D) in impaired DC migration to DLN and age-related susceptibility to SARS-CoV infection [107] . PLA 2 G2D is upstream of PGD 2 in the prostaglandin synthesis pathway. Both molecules may be useful targets for anti-viral therapies. As mentioned above, SARS-CoV nucleocapsid protein was reported to interfere with RIG-I ubiquitination [96] , while decreased deubiquitination mediated by MERS-CoV nsp3 deubiquitinase also inhibited the host immune response [108] . Recently, Fehr et al. found that mutation of the macrodomain of nsp3, important for countering ADP-ribosylation, resulted in virus attenuation [109] , while another report demonstrated that binding of the methyl donor S-adenosyl-L-methionine (SAM) to 2 0 -Omethyltransferase nsp16 enhanced MERS-CoV replication, promoting the recruitment of the allosteric activator nsp10 [110] . On the other hand, IAV induced host histone deacetylase 1 dysregulation in lung epithelial cells, inhibiting IAV infection [111] while NEDDylation (conjugation of a ubiquitin-like protein, neural precursor cell expressed developmentally down-regulated 8 (NEDD8)) of PB2 protein reduced its stability, suppressing IAV replication [112] . Nevertheless, the role of epigenetic modification during respiratory virus infection is not well understood; the application of phosphoproteomics to characterization of the human macrophage response to IAV infection [113] serves as a model for future studies. Other putative targets for modulating the immune response are carbohydrates present on host and viral proteins. Recently, integrated omics and computational glycobiology revealed the structural basis for IAV glycan microheterogeneity and host interactions [114, 115, 116] . Glycosylation of the HA protein not only mediated virus entry into host cells [115] [116] [117] , but also modulated IAV replication and transmission [118] , and the immune response against the virus [119] [120] [121] , thus representing a potential target for vaccine and drug development [122, 123 ] . Vaccines remain as the most efficient tools for preventing the occurrence and spread of viral respiratory diseases. Distinct from conventional adjuvants, novel reagents are being used to shape as well as augment the strength of the induced immune responses. Targeting IAV HA to the chemokine receptor, Xcr1, present on some dendritic cells enhanced protective antibody responses against the virus [124] . In addition, knowledge of the microbiota [125] , and manipulation of apoptosis [126] and mTOR (mechanistic target of rapamycin) [127] -related signaling pathways have been used to predict or modulate responsiveness and efficiency of vaccines, respectively. A major goal of IAV and CoV vaccine development is to develop vaccines able to induce broadly acting antibodies; these efforts require more precise definition of useful conserved protective antibody epitopes [128] . Further, monocytederived dendritic cells (moDCs) [129] dominated the activation of CD8+ T cells at late times after infection of C57BL/6 mice, triggering a switch in immunodominance from PA to NP-specificity. This differential expression of T cell epitopes has implications for DC-based vaccine design. Additionally, neutrophil-targeting [42] and Th1-targeting strategies [130] might help in establishing tissue-resident memory (TRM) and heterosubtypic immunity. Inducing effective resident immune memory represents an ideal strategy for protecting the host from respiratory virus infection, especially at very early phases of virus invasion. Recent technical advances have facilitated distinguishing tissue-resident cell populations from those in the periphery. In a recent publication, airway memory CD4(+) T cells induced by a single conserved N proteinspecific epitope present in both SARS-CoV and MERS-CoV mediated protection against challenge with either pathogen [131 ] . IAV-specific resident memory CD8 cells in the upper respiratory tract or bronchoalveolar fluid provided superior protection compared to those in the lung, although some studies questioned whether these were truly resident memory as opposed to memory cells at these sites [132] . In a recent report, Slutter et al. delineated the dynamics of IAV-induced lung-resident memory T cells that underlies waning heterosubtypic immunity [133] , illustrating the tight collaboration of resident and peripheral T cell memory in respiratory virus control. In the future, use of sophisticated cell sorting methods and mass spectrometric flow cytometry will provide more precise information about resident memory immune cells. The IAV-specific antibody response is well known to be a key host factor in protection from subsequent challenge [134, 135] . Recent work has identified nasopharyngeal protein biomarkers in immunized mice useful for predicting the severity and outcome of acute respiratory virus infection [136] . Other studies have identified an important synergistic role for immune responses in inducible bronchus-associated lymphoid tissue (iBALT) and draining lymph nodes for optimal IAV-specific CD4+ T cell responses [137] . In contrast, nasal-associated lymphoid tissues (NALTs) have been shown to support the recall but not priming of IAV-specific cytotoxic T cells [138 ] . Genomics, next-generation sequencing [139] and single cell imaging and analysis [140] facilitated in-depth investigation of the evolution, recombination and spread of infectious pathogens and extend the scope of virology research. In addition to these molecular biology tools, methods such as analyses of DC responses [141] and digital cell quantification (DCQ), which combine genome-wide gene expression data with immune cell functional studies, will help identify immune cell subpopulations [142] . Especially critical for understanding the ecology of RNA viruses, such as IAV and CoV, will be obtaining respiratory samples from camels (MERS-CoV) and patients in both cross-sectional and longitudinal studies. These samples will be useful for identifying carriers and understanding virus evolution and transmission dynamics [143, 144] . Recent analyses of MERS-CoVinfected camels [145] have also increased our knowledge of virus demography and evolution across diverse populations. Although gene sequencing and crystallographic analyses have provided insight into the molecular evolution of IAV, the inability to predict future virus evolution remains an obstacle in managing epidemic and pandemic spread. Models using canalized evolutionary trajectory induced by selective dynamics [146] , intra-host IAV dynamics [147] , sequence based epidemiology [148] , genomic diversification and adaptation during experimental serial passages [149] will help in the development of accurate prediction models. However, successful modeling to prospectively predict the emergence of new virus strains relies on solid experimental data obtained from field investigations. The standardization of protocols and normalization of data are key challenges in developing useful models of virus evolution. This brief review outlines how the host immune response plays both protective and pathogenic roles in respiratory virus infections. To decrease the burden that respiratory viruses place on society, increased understanding of all aspects of the host immune response remains a critical research goal. Host genetic determinants of influenza pathogenicity Host genetics of severe influenza: from mouse Mx1 to human IRF7 Population diversity and collective interactions during influenza virus replication and evolution Influenza A Immunomics and Public Health Omics: the dynamic pathway interplay in host response to H1N1 infection Integrated Omics analysis of pathogenic host responses during pandemic H1N1 influenza virus infection: the crucial role of lipid metabolism Crucial role of lipid metabolism in IAV infection was illustrated USING integrated omics analysis Epigenetic landscape during coronavirus infection Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection Interaction between macrophage and epithelial cells exacerbated disease severity by inhibitIng lung edema clearance Alveolar macrophages prevent lethal influenza pneumonia by inhibiting infection of type-1 alveolar epithelial cells Aveolar macrophage prevented lethal pneumonia by inhibiting IAV infection on epithelial cells Innate immunity and the inter-exposure interval determine the dynamics of secondary influenza virus infection and explain observed viral hierarchies Non-linear enhancement of mRNA delivery efficiencies by influenza A derived NS1 protein engendering host gene inhibition property The RNA-and TRIM25-binding domains of influenza virus NS1 protein are essential for suppression of NLRP3 inflammasome-mediated IL-1beta secretion A: Induction and evasion of type I interferon responses by influenza viruses Influenza virus NS1 protein binds cellular DNA to block transcription of antiviral genes The Cterminal effector domain of non-structural protein 1 of influenza A virus blocks IFN-beta production by targeting TNF receptor-associated factor 3 The role of N-terminustruncated NS1 proteins of influenza A virus in inhibiting IRF3 activation Influenza A virus virulence depends on two amino acids in the N-terminal domain of its NS1 protein facilitating inhibition of PKR Neuraminidase-mediated, NKp46-dependent immuneevasion mechanism of influenza viruses BST-2 restricts IAV release and is countered by the viral M2 protein Nuclear imprisonment: viral strategies to arrest host mRNA nuclear export Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import Influenza overcomes cellular blocks to productively replicate impacting macrophage function To conquer the host, Influenza virus is packing it in: interferon-antagonistic strategies beyond NS1 Double PHD Fingers 2 (DPF2) promotes the immune escape of influenza virus by suppressing interferon-beta production Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages RNA-virus proteases counteracting host innate immunity SARS coronavirus nucleocapsid inhibits type I interferon production by interfering with TRIM25-Mediated RIG-I ubiquitination Autophagosomal protein dynamics and influenza virus infection Influenza virus infection induces host pyruvate kinase M which interacts with viral RNAdependent RNA polymerase Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2 0 -O methylations ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death Going against the tide: selective cellular protein synthesis during virally induced host shutoff HA triggers the switch from MEK1 SUMOylation to phosphorylation of the ERK pathway in influenza A virusinfected cells and facilitates its infection Highly pathogenic avian influenza H5N1 virus delays apoptotic responses via activation of STAT3 Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy Activated NOX2 exacerbated virus-mediated pathogenicity via production of reactive oxygen species (ROS) Proteomic analysis of differential expression of cellular proteins in response to avian H9N2 virus infection of A549 cells Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection Molecular dynamic studies of interferon and innate immunity resistance in MERS CoV Non-Structural protein 3 The conserved coronavirus macrodomain promotes virulence and suppresses the innate immune response during severe acute respiratory syndrome coronavirus infection Binding of the methyl donor SAM to MERS-CoV 2 0 -Omethyltransferase nsp16 promotes the recruitment of the allosteric activator nsp10 Influenza A virus dysregulates host histone deacetylase 1 that inhibits viral infection in lung epithelial cells NEDDylation of PB2 reduces its stability and blocks the replication of influenza A virus Phosphoproteomics to characterize host response during influenza A virus infection of human macrophages Integrated omics and computational glycobiology reveal structural basis for Influenza A virus glycan microheterogeneity and host interactions Glycosylation changes in the globular head of H3N2 influenza hemagglutinin modulate receptor binding without affecting virus virulence Permissivity of DPP4 orthologs to MERS-Coronavirus is governed by glycosylation and other complex determinants Influenza virus-glycan interactions Progressive glycosylation of the hemagglutinin of avian influenza H5N1 modulates virus replication, virulence and chicken-to-chicken transmission without significant impact on antigenic drift Playing hide and seek: how glycosylation of the influenza virus hemagglutinin can modulate the immune response to infection Glycosylation characterization of an influenza H5N7 hemagglutinin series with engineered glycosylation patterns: implications for structure-function relationships Glycosylation of the HA protein of H5N1 virus increases its virulence in mice by exacerbating the host immune response Unmasking stemspecific neutralizing epitopes by abolishing N-linked glycosylation sites of influenza hemagglutinin proteins for vaccine design Influenza A surface glycosylation and vaccine design Targeting influenza virus hemagglutinin to Xcr1+ dendritic cells in the absence of rReceptor-mediated endocytosis enhances protective antibody responses The potential of the microbiota to influence vaccine responses Apoptosis and other immune biomarkers predict influenza vaccine responsiveness Influenza vaccines: mTOR inhibition surprisingly leads to protection Evolution in the influenza A H3 stalk -a challenge for broad-spectrum vaccines? Monocyte-derived dendritic cells enhance protection against secondary influenza challenge by controlling the switch in CD82 T-cell immunodominance Virus-like particle vaccine primes immune responses preventing inactivated-virus vaccine-enhanced disease against respiratory syncytial virus Airway memory CD4(+) T cells mediate protective immunity against emerging respiratory coronaviruses Conserved epitopes-specific airway memory CD4(+) T cells induced by vaccine protected animals from SARS-CoVs and MERS-CoV infection Resident memory CD8+ T cells in the upper respiratory tract prevent pulmonary influenza virus infection Dynamics of influenza-induced lungresident memory T cells underlie waning heterosubtypic immunity Heads, stalks and everything else: how can antibodies eradicate influenza as a human disease Antibodydependent cellular cytotoxicity and influenza virus Inducible bronchus-associated lymphoid tissue (iBALT) synergizes with local lymph nodes during antiviral CD4(+) T cell responses Nasal-associated lymphoid tissues (NALTs) support the recall but not priming of influenza virusspecific cytotoxic T cells NALTs support the recall but not priming of IAV-specific cytotoxic T cells New-generation screening assays for the detection of anti-influenza compounds targeting viral and host functions Visualization of IAV genomes at the single-cell level Human dendritic cell response signatures distinguish 1918, pandemic and seasonal H1N1 influenza viruses Digital cell quantification identifies global immune cell dynamics during influenza infection Natural history of highly pathogenic avian influenza H5N1 Middle East respiratory syndrome Longitudinal study of Middle East respiratory syndrome coronavirus infection in dromedary camel herds in Saudi Arabia Canalization of the evolutionary trajectory of the human influenza virus Within-host influenza dynamics: a small-scale mathematical modeling approach Dynamically correlated mutations drive human Influenza A evolution Quantitative modeling of virus evolutionary dynamics and adaptation in serial passages using empirically inferred fitness landscapes Supported in part by grants from the NIH (NIAID, PO1 AI060699, RO1 AI129269).