key: cord-011438-imbpgsub
authors: Zhang, Yun; Xu, Zhichao; Cao, Yongchang
title: Host–Virus Interaction: How Host Cells Defend against Influenza A Virus Infection
date: 2020-03-29
journal: Viruses
DOI: 10.3390/v12040376
sha: 
doc_id: 11438
cord_uid: imbpgsub

Influenza A viruses (IAVs) are highly contagious pathogens infecting human and numerous animals. The viruses cause millions of infection cases and thousands of deaths every year, thus making IAVs a continual threat to global health. Upon IAV infection, host innate immune system is triggered and activated to restrict virus replication and clear pathogens. Subsequently, host adaptive immunity is involved in specific virus clearance. On the other hand, to achieve a successful infection, IAVs also apply multiple strategies to avoid be detected and eliminated by the host immunity. In the current review, we present a general description on recent work regarding different host cells and molecules facilitating antiviral defenses against IAV infection and how IAVs antagonize host immune responses.

Influenza A virus (IAV) can infect a wide range of warm-blooded animals, including birds, pigs, horses, and humans. In humans, the viruses cause respiratory disease and be transmitted by inhalation of virus-containing dust particles or aerosols [1] . Severe IAV infection can cause lung inflammation and acute respiratory distress syndrome (ARDS), which may lead to mortality. Thus, causing many influenza epidemics and pandemics, IAV has been a threat to public health for decades [2] .

The virus is an enveloped, segmented, negative-strand RNA virus, belonging to the Orthomyxoviriae family. The eight viral gene segments encode as many as 18 proteins. Besides polymerase basic 1 (PB1), PB1-N40, PB1-F2, PB2, polymerase acid (PA), hemagglutinin (HA), nucleoprotein (NP), neuraminidase (NA), matrix 1 (M1), matrix 2 (M2), nonstructural protein 1 (NS1) and NS2 (also known as nuclear export protein, NEP), new viral proteins were recently uncovered, such as PB2-S1 [3] , PA-X (product of ribosomal frameshifting) [4] , PA-related proteins PA-N155 and PA-N182 [5] , M42 [6] , and NS3 [7] . HA, NA, and M2 proteins constitute surface of the IAV virion, where HA is the most abundant surface protein. According to the genetic and antigenic diversity of the HA and NA proteins, IAVs were divided into 18 HA and 11 NA subtypes. H17N10 and H18N11 subtypes were recently identified in bats [8, 9] .

HA is a type I glycosylated protein, which is responsible for virus entry to host cell. Functional HA protein is a homotrimer structurally composed of a stem region and a globular head region in each monomer. The head region bearing N-acetylneuraminic acid (sialic acid, SA) binding pocket is critical for receptor attachment, and contains most antigenic determinants. The stem region undergoing conformational changes is responsible for low pH-triggered membrane fusion [10] , and plays an important role in cross protection against heterosubtypic IAV infection [11] . N38 glycan at this region

IAVs can infect a broad spectrum of host species, including both wild and domestic birds, as well as many mammalian species. The virus is capable of interspecies transmission to new species. However, no interspecies transmission of the bat IAVs has been reported so far [54] . Furthermore, the high frequency of mutations and recombination increases the risk of IAV adaptation in humans. Besides three pandemic subtypes (H1N1, H2N2, and H3N2), other subtypes, including H5N1, H5N6, H7N7, H7N9, N9N2, and H10N8 could cross the species barrier and cause human infections [55] [56] [57] [58] . Several effect factors are essential in IAV host switch events, including the receptor-binding properties of HA [16] , as well as cellular receptors [59] [60] [61] [62] . Long and his colleagues summarized the role of host factors in IAVs adaption to humans, and the review is recommended here for further reading [63] .

Noteworthy is the fact that most phylogenetically diverse IAVs with different origins could successfully replicate in swine [64] . Since pigs have both SA α-2,6 and SA α-2,3 galactose receptors [65] , they can serve as a suitable mixing reservoir for both human and avian IAVs, thus raising global concern on periodic zoonotic infections. Take the emergence of influenza A (H1N1) pdm09 (pH1N1) and influenza A (H3N2) A/Canada/1158/2006 strains for instance, both strains are swine-origin IAVs and were the consequence of adaption and reassortment of several swine lineages [66, 67] . Furthermore, some genes of these strains originated from avian IAVs [68] .

With the development of gene sequencing technology, machine learning (ML) facilitated with large genomic datasets are used in prediction about sequence changes in newly invaded viruses from other animal hosts, take the "Batch-Learning Self-Organizing Map (BLSOM)" method for instance [69] . ML is also applied in characterization of distinct host tropism protein signatures [70] , and prediction of amino acid changes for interspecies transmission [71] . These studies provided measures in identification of potential high-risk strains. In addition, the nucleotides and dinucleotide compositions of viruses play important roles in prediction of viral host species [72] . Combining gene sequencing technology Viruses 2020, 12, 376 4 of 23 and ML methods, researchers applied large IAV genomic datasets to analyze species selection bias of IAV mono-/dinucleotide composition and predict human-adaptive swine or avian IAVs [73, 74] . The application of multi-disciplinary subjects would provide useful information for prediction of pandemic influenza.

In general, the life cycle of the IAV is generally divided into four steps: virus entry into the host cell, transcription and replication of the viral genome, assembly, and virus budding. Though alveolar epithelial cell is the primary target cell for IAVs, different IAV subtypes have different patterns of viral attachment (PVA). For human IAVs, Alveolar type II epithelial cells, as well as immune cells such as alveolar macrophages and dendritic cells, are major target cells for an established infection [75, 76] . Two seasonal IAVs and pandemic H1N1 virus, preferred to attach to ciliated epithelial cells and goblet cells in the upper respiratory tract (URT), and avian IAVs, take H5N1 for instance, attached seldom to these cells [77] . In the lower respiratory tract (LRT), human IAV H1N1 and H3N2 attached to more cell types than avian IAV H5N1, a highly pathogenic avian IAV (HPAIV) strain. However, H5N1 could bind to type II pneumocytes [78] . Considering the fact that metabolism in the type II pneumocytes is quite active, infection of HPAIVs is more likely to cause severe pneumonia [78] . Other research on low pathogenic avian IAVs (LPAIVs), which generally do not cause severe pneumonia, showed that these viruses usually attach to human submucosal gland cells, thus can be cleared by the mucus [79] .

IAV infection starts from recognition of SA by HA protein, though in vitro research claimed that these N-linked glycans were not essential for virus entry [80] . The cleavage of HA precursor protein HA0 into HA1 (containing receptor binding domain) and HA2 (containing fusion peptide) in low pH environment during HA transport is critical for virion internalization [81] . Some research showed that type II transmembrane serine protease such as transmembrane protease serine 2 (TMPRSS2), human airway trypsin-like protease (HAT), transmembrane protease serine 4 (TMPRSS4), Homo sapiens serine protease DESC1 and Homo sapiens transmembrane protease, serine 13 (MSPL) can cleave human and avian IAV HA proteins at an arginine residue [82] . In addition, for avian IAVs, HA0 of HPAIVs can be cleaved by subtilisin-like protease, while that of LPAIVs is cleaved by trypsin-like proteases [83] or thrombin [84] . Therefore, in avian IAVs, the cleavage sites are considered to be the major determinants for virus virulence [85] , and RNA folding in the cleavage region could be an important factor for virulence determination [86, 87] .

Proteins in the vRNP complex contain different nuclear localization signals (NLSs), thus helping the vRNP complex to enter the host cell nucleus via active transport, take the Crm1-dependent pathway for instance [88] . The acidic environment of the endosome also activates M2 ion channel, hence acidifies the viral core, resulting in entrance of vRNP complex into the host cell [34] . Replication of viral genome does not require a primer but a full-length complementary RNA (cRNA), which is essential for the newly formed vRNP complex. The viral RNA polymerases first bind to the 3 end and the 5 end of the segmented viral RNA and cRNA, respectively, then start replication with the help of the 5 cap of host pre-mRNAs via a PB1-PB2-mediated "cap snatching" mechanism [27, 89] . The conserved segment-specific nucleotides at the 3 and 5 ends of the viral genome could modulate genome expression and replication during infection [90] . In addition, dephosphorylation at a specific position of the H1N1 NS1 protein results in attenuated virus replication [91] .

Mature viral mRNAs are transported to the cytoplasm by a "daisy-chain" complex and translated subsequently [88, 92] . New synthesis of HA occurs on the rough endoplasmic reticulum (ER). Glycosylation and palmitoylation of the protein are completed later in the Golgi [93, 94] . After synthesis and maturation of NA and M2 proteins, the trans-Golgi network (TGN), together with coat protein I (COPI) complex and GTPase Rab proteins, transport the newly synthesized HA, NA, and M2 proteins to the apical plasma membrane (PM). These proteins then assemble with viral genomic segments. The virions are finally closed and M1 and M2 proteins mediate virion budding from the apical side of the Viruses 2020, 12, 376 5 of 23 cells [28, [95] [96] [97] [98] . NA protein cleavages the SA residues, which allows the virions to be released from the plasma membrane [99] .

Since IAV has a relatively small genome, host machinery is required in order to accomplish the viral life cycle. To uncover host dependency factors that are necessary for IAV replication, numerous large-scale RNA interference (RNAi) screens and genome-wide CRISPR/Cas 9 screen were performed [29, [100] [101] [102] [103] . For instance, SON DNA binding protein was important for IAV virion trafficking in an early infection stage and CDC-like kinase 1 facilitated AIV replication [29] . USP47 facilitated viral entry, whereas TNFSF12 (APRIL) and TNFSF12-TNFSF13 (TWEPRIL) helped with viral replication [101] . Using genome-wide CRISPR/Cas9 screen, several genes of sialic acid biosynthesis and related glycosylation pathways were involved with H5N1 infection [102] , and WDR7, CCDC115, and TMEM199 were essential for viral entry and regulation of V-type ATPase assembly [103] . Furthermore, single-cell transcriptome sequencing (RNA-seq) was applied to explore host-virus interactions, revealing a correlation between defective viral genomes and virus-induced host transcriptional programs [104] . These data provide valuable information for developing host-targeted therapeutics.

Host immune system functions immediately after detection of the virus. Host mucosal immune system (MIS), induced after virus invasion, serves as the first line to prevent IAV from adhering to the susceptible cells. In the URT, mucosal response is induced in the naso-associated lymphoid tissues (NALT), while in the LRT, it occurs in bronchus-associated lymphoid tissues (BALT). Host innate immunity, including phagocytic cells, interferons (IFNs), proinflammatory cytokines, etc., applies multiple mechanisms in defending IAV infection [105] . Host adaptive immunity, mediated by B lymphocytes and T lymphocytes, together with other immune mechanisms, reacts specifically to neutralize and eliminate the virus. On the other hand, to establish a successful infection, IAVs also employ a plethora of strategies to avoid being detected or being cleared by the host immunity. Notable strategies include regulation of IFN signaling [106] , inhibition of cytokine expressions [107, 108] , modulation of apoptosis [109] [110] [111] , interference of autophagy [112] , and effects on antibody production [113] . The IAV-host immunity interaction was summarized by several reviews [114, 115] .

Upon detection of infection, innate effector cells, including natural killer (NK) cells, neutrophils, and dendritic cells (DCs), etc., are recruited to the infected sites. NK cells are large granular lymphocytes, making up 10% of the resident lymphocytes in the lung. After recruitment from the blood, NK cells interact with DCs and macrophages to secret various cytokines and restrict infection via lysis of the IAV-infected cells. The lysis process is mediated by interaction between NK receptors p46 (most NKp46) and IAV HA protein expressed by the infected cell [116, 117] . Interestingly, liver NK cells other than lung NK cells possessed a memory phenotype to protect mice against subsequent IAV infection, though the lung NK cells are important in control of primary IAV infection [118] . However, NK cells are also shown to exacerbate IAV pathology, since depletion of NK cells led to increased resistance to high dose H1N1 infection in mice [119, 120] . The contribution of NK cells to anti-IAV defense in mouse models was later shown to be strain and dose dependent. In addition, the host genetic background also played an important role [121] .

Neutrophils are key innate immune cells recruited to infection sites by cellular migration through vascular endothelium. They function in clearance of pathogens via phagocytosis, producing extracellular traps, and degranulation [122] . In addition, they also regulate adaptive immunity via guiding influenza specific CD8 + T cells to the infection sites [123] .

The function of dendritic cells (DCs) is to monitor invading pathogens. After IAV infection, the conventional DCs migrate from lung to lymph nodes through interaction between CCR7 and its ligand, and present antigens to T cells [124, 125] . One study based on a mouse model showed that, during IAV infection, immature and mature DCs were specialized in IAV HA processing, since both types of DCs could present one epitope of H1N1 HA (HA amino acids 107-119), whereas another epitope (HA amino acids 302-313) could only be processed by mature DCs [126] . The complex role of DCs in initiation of robust immunity against IAV infection is reviewed by Waithman and Mintern [127] .

T cells and B cells are critical components in adaptive immunity against IAV infection. CD8 + T cells differentiate into cytotoxic T lymphocytes (CTLs) and defend IAV infection via producing cytokines and effector molecules, and cytotoxic effects (i.e., lysis) of infected cells mediated by MHC class I. CD4 + T cells target IAV-infected epithelial cells through binding with MHC class II molecules and contribute to B cell activation thus consequently promote antibody production. The activation of T cells and B cells in IAV infection will be exposited in Section 3.5.

The reaction of innate immunity is nonspecific. It is triggered by recognition of pathogen associated molecular patterns (PAMPs) via host pathogen recognition receptors (PRRs). Toll-like receptors (TLRs), retinoic acid-inducible gene-I proteins (RIG-I), and NOD-like receptors are common PRRs, the activation of which leads to activation of innate immune signaling and further production of cytokines as well as other antiviral molecules.

Toll-like receptors are responsible for sensing pathogens at cell membranes, endosomes, and lysosome [128] . TLR3 and TLR7 are shown to be involved in IAV detection at endosomes [105] . TLR3 recognizes double stranded RNA (dsRNA) which may be released by cellular stress and cell death [105] and unidentified RNA structures in phagocytosed cells infected with IAVs [129] . In macrophages and dendritic cells, TLR3 interacted with TIR-domain-containing adapter, then activated the serine-threonine kinase IκKε (IKKε) and TANK binding kinase 1 (TBK1) to phosphorylate interferon regulatory factor 3 (IRF3), the process of which further led to expression of IFN-β [130] . In addition, an over-reacting TLR3 activation promoted IAV pathogenesis, which could be reduced by a single-stranded oligonucleotide (ssON) functioning as a TLR3 inhibitor, resulting in restrained viral loads both in vitro and in vivo [131] . TLR7 recognizes single stranded RNA (ssRNA). In plasmacytoid dendritic cells (pDCs), after activation of TLR7 during IAV infection, IRF7 or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were activated via myeloid differentiation factor 88 (MyD88) to induce type I IFNs [132] . In avian macrophages, activation of TLR7 produced pro-inflammatory molecules such as interleukin (IL)-1β [133] . In addition, in mouse models, TLR7 played an important role in activation of NK cells [134] . It was also shown to be involved in development of adaptive immunity to prevent IAV infection [135, 136] .

RIG-I recognizes ssRNAs and transcriptional products of IAVs, which triggers activation of the caspase activation and recruitment domains (CARDs) via dephosphorylation or ubiquitination by E3 ligases, resulting in activation of transcription factors including IRFs and NF-κB [137] . OTUB1 played an essential role in regulation of RIG-I [138] . In addition, melanoma differentiation-associated gene 5 (MDA5) was also involved in sensing transcriptional products of IAVs in the cytoplasm [139] .

For NOD-like receptor family, pyrin domain containing 3 (NLRP3) and NLR apoptosis inhibitory protein 5 were activated after IAV infection [140] . IAV M2 ion channel and PB1-F2 were involved in activation of NLRP3 inflammasome and stimulate IL-1β secretion subsequently [141, 142] . The role of the NLRP3 inflammasome in regulation of anti-IAV responses is discussed in detail by Sarvestani and his colleagues [143] . Delayed oseltamivir and sirolimus combined treatment could suppress NLRP3 inflammasome mediated secretion of IL-1β and IL-18, resulting in attenuation of H1N1-induced lung injury [144] .

After detecting viral components, transcription factors including NF-κB and IRFs are activated, leading to transcription of IFNs and pro-inflammatory cytokines. IFNs bind to receptors, resulting in upregulation of multiple interferon-stimulated genes (ISGs) [145] . It is well known that type I IFNs Viruses 2020, 12, 376 7 of 23 (IFN-α and IFN-β) and type III IFNs (IFN-λ 1-4) play critical roles in antiviral responses. Mice failed to restrict non-pathogenic IAV when both type I and type III IFN receptors were knocked out [146] .

The expressed IFNs consequentially bind to different receptors. Type I IFNs interact with IFN-α/β receptors (IFNAR), whereas type III IFNs interact with IFN-λ receptors (IFNLR). Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is then activated, resulting in transcription of numerous IFN-stimulated genes (ISGs) [147, 148] . Though IFN-λs share many characteristics such as expression patterns, signaling pathways, etc. with type I IFNs, they are the first IFNs produced at the infected epithelial sites to block virus spread [149] . Furthermore, IFN-λs served an important role in programming DCs to direct effective T cell immunity against IAV infection [150] .

ISGs encode various antiviral proteins functioning in different ways to defend IAV infection. For instance, MxA GTPase from the Mx family could retain viral genome from entry to the cytoplasm via blocking the function of IAV NP. In addition, in vitro research found that avian IAVs were more sensitive to MxA than human IAVs [151, 152] . Cholesterol 25-hydroxylase (CH25H) were identified to block IAV entry via altering the cellular membrane properties to interfere with viral fusion, and amplified the activation of immune cells [153] . Guanylate-binding protein 3 (GBP3) of IFN-inducible GTPases inhibited IAV replication via binding to the viral polymerase complex [154] . Members of the tripartite motif-containing (TRIM) family are also involved in cellular anti-IAV processes. For instance, TRIM14 could interact with IAV NP for ubiquitination and proteasomal degradation, thus restricting IAV replication in a type I IFN and NF-κB independent manner [155] . TRIM22 degraded IAV NP via polyubiquitination, thus resulting in inhibition of IAV infection [156] . TRIM 25 regulated the re-localization of RIG-I and was responsible for RIG-I ubiquitination as well as RIG-I-mediated IFN production [157] . TRIM32 recognized IAV PB1 protein and reduced its polymerase activity [158] . TRIM41 targeted NP for ubiquitination and degradation in vitro [159] . For further reading on other ISGs, several reviews regarding IFN responses during IAV infection are recommended here [160, 161] . A general description of activation of innate immunity and IFN signaling pathway after IAV infection is illustrated in Figure 1 . signal transducer and activator of transcription (JAK-STAT) signaling pathway is then activated, resulting in transcription of numerous IFN-stimulated genes (ISGs) [147, 148] . Though IFN-λs share many characteristics such as expression patterns, signaling pathways, etc. with type I IFNs, they are the first IFNs produced at the infected epithelial sites to block virus spread [149] . Furthermore, IFNλs served an important role in programming DCs to direct effective T cell immunity against IAV infection [150] .

ISGs encode various antiviral proteins functioning in different ways to defend IAV infection. For instance, MxA GTPase from the Mx family could retain viral genome from entry to the cytoplasm via blocking the function of IAV NP. In addition, in vitro research found that avian IAVs were more sensitive to MxA than human IAVs [151, 152] . Cholesterol 25-hydroxylase (CH25H) were identified to block IAV entry via altering the cellular membrane properties to interfere with viral fusion, and amplified the activation of immune cells [153] . Guanylate-binding protein 3 (GBP3) of IFN-inducible GTPases inhibited IAV replication via binding to the viral polymerase complex [154] . Members of the tripartite motif-containing (TRIM) family are also involved in cellular anti-IAV processes. For instance, TRIM14 could interact with IAV NP for ubiquitination and proteasomal degradation, thus restricting IAV replication in a type I IFN and NF-κB independent manner [155] . TRIM22 degraded IAV NP via polyubiquitination, thus resulting in inhibition of IAV infection [156] . TRIM 25 regulated the re-localization of RIG-I and was responsible for RIG-I ubiquitination as well as RIG-I-mediated IFN production [157] . TRIM32 recognized IAV PB1 protein and reduced its polymerase activity [158] . TRIM In order to counter IFN-stimulated antiviral proteins, IAV viral proteins apply multiple strategies. For instance, HA protein was shown to trigger ubiquitination of IFNAR to attenuate the type I IFN signaling pathway [162] . The follow-up work showed that poly (ADP-ribose) polymerase 1 (PARP1) functions as an interacting partner of HA protein to mediate the HA-induced IFNAR degradation [163] . NS1 is the most important IFNs antagonist protein via mechanisms including inhibition of the TRIM25-mediated RIG-I ubiquitination, suppression of protein kinase R (PKR), In order to counter IFN-stimulated antiviral proteins, IAV viral proteins apply multiple strategies. For instance, HA protein was shown to trigger ubiquitination of IFNAR to attenuate the type I IFN signaling pathway [162] . The follow-up work showed that poly (ADP-ribose) polymerase 1 (PARP1) functions as an interacting partner of HA protein to mediate the HA-induced IFNAR degradation [163] . NS1 is the most important IFNs antagonist protein via mechanisms including inhibition of the TRIM25-mediated RIG-I ubiquitination, suppression of protein kinase R (PKR), phosphorylation of IκB kinases (IKK) α and β in the NF-κB pathway, interruption of the phosphorylation of STAT1, STAT2, and STAT3 [39, 115] , and degradation of OTUB1 [138] . Phosphorylation of NS1 is crucial for its function of antagonizing IFN-β expression, since dephosphorylation at position 73 and 83 of the protein induced a high level of IFN-β [91] . Non-structural protein PB1-F2, identified from a+1 open reading frame (ORF) of PB1 gene segment [164] , is multifunctional in deregulation of type I interferon [165, 166] . It counteracted RLR-mediated activation of IFN pathway not only by targeting mitochondrial MAVS [115, 165, 167] , but also by binding to the DEAD-box helicase DDX3 to induce proteasome-dependent degradation [166] . Furthermore, PB1-F2 interacted with mitochondrial Tu translation elongation factor (TUFM) to mediate formation of autophagosome, thus inducing complete mitophagy, which is critical for MAVS degradation [167] . Novel PA-X protein could also modulate innate immune responses. A review regarding the function of NS1 and PA-X proteins in antagonizing host innate immunity is recommended here [114] .

Though autophagy is essential for cellular metabolism and homeostasis, it also plays important roles in innate immune responses against pathogen infection. For cellular homeostasis, the mTOR pathway is one of the most conserved autophagic pathways. The mTOR complex 1 (MTORC1) negatively regulates the ULK1 kinase activity, thus affecting the autophagy induction [168] . c-Jun N-terminal protein kinase 1 (JNK1) disrupts the Bcl-2/Beclin-1 complex through phosphorylation, thus regulating the autophagy induction [169, 170] . JNK1 is also reported to upregulate Beclin-1 expression through phosphorylation of transcription factor c-Jun in vitro [171] .

In contrast to the autophagic pathways for cellular metabolism and homeostasis, less is known about autophagosome formation after IAV infection [172] . To restrict infection of multiple viruses including IAVs, TRIM23 is essential to mediate autophagy via its RING E3 ligase and ADP-ribosylation factor (ARF) GTPase activity [173] . Beclin-1 and TUFM-regulated autophagy also inhibited IAV replication [112] . In HeLa cells and A549 cells, IAV infection activated JNK1 to induce autophagosome formation and TGF-β-activated kinase 1 might contribute to the process [174, 175] . Furthermore, autophagy was involved in maintaining memory B cells to counteract IAV infection [176] .

IAV also utilizes autophagy to complete its life cycle. NS1 protein is proposed to suppress JNK1-mediated autophagy induction [174] . M2 could also block autophagosome maturation and mediate microtubule-associated protein 1 light chain 3 (LC3)-bound membrane redistribution, thus allowing filamentous budding of IAV [177] [178] [179] . Circ-GATAD2A (GATA zinc finger domain containing 2A), induced by IAV infection, could inhibit autophagy and promote IAV replication [180] . For a comprehensive reading on IAV-induced apoptosis, a review is recommended here [181] .

Upon detection of IAVs, DCs trigger production of IFNs and cytokines, which in turns assist maturation of the DCs into antigen presenting cells (APCs), and initiate T cell immune responses. Through the activation of Ag-bearing DCs, naïve CD4 + T cells differentiate into Th1, Th2, Th7, regulatory T cells (Treg cells), follicular helper T cells, and killer cells. Th1 and follicular helper T cells are the most abundant CD4 + T helper cells. They can secret antiviral cytokines, regulate CD8 + T cell differentiation, promote B cell activation, and maintain immunological memory [182, 183] . Th17 cells induced pulmonary pathogenesis and could decrease mortality of IAV-infected mice [184, 185] . In addition, γδ T cells, expanding in the late stage of IAV infection with a T cell receptor (TCR)-independent Viruses 2020, 12, 376 9 of 23 manner, could efficient eliminate IAV-infected airway epithelial cells, resulting in lower viral titers [186] . New surrogate markers CD49d and CD11a were used to explore the kinetics of IAV-specific CD4 T cells responses, revealing endogenous CD4 T cell response to primary IAV infection is predominantly composed of T-bet+ cells [187] .

CD8 + T cells are major components for virus clearance in adaptive immunity. After activated by DCs, CD8 + T cells undergo rapid expansion, differentiation, and migration to the infected sites. In general, to establish effective primary cytotoxic T lymphocyte (CTL) responses, CD4 + T cells play an essential role, with a mouse model as an exception [188] . CTLs produce cytotoxic granules containing perforin and granzymes (GrA and GrB) to induce apoptosis and interrupt IAV replication [189] . In addition, CTLs produce cytokines, such as TNF, FASL, and TRAIL, which recruit death receptors to induce apoptosis [190] . In addition, IL16 deficiency enhanced the Th1 and CTL responses upon IAV infection [191] . Furthermore, as CD8 + cells could last for two years in murine models, IAV-specific memory CTLs reacted specific to epitopes in conserved IAV proteins [192] . In the nasal epithelia, they could prevent the spread of the virus from the URT to the lung [193] . To establish memory CD8 + T cells, autophagy plays an important role [194] , while the function of CD4 + T cells in memory CTL responses is "context-dependent". A recent study showed that CD4+ T cells promoted IAV-specific CTL memory at the initial priming stage of viral infection [195] . Grant and her colleagues summarized and discussed the importance of CD8 + T cell immunity against IAVs [192] , and this review is recommended for further reading.

With the help of CD40 ligand (CD40L), CD4 + cells contribute to B cell activation [183] . With the help of memory T cells, naïve B cells could reduce morbidity and promote recovery on heterosubtypic infection [196] . For different types of antibodies, IgG could inhibit pathogenesis, while IgA functions in blocking IAV transmission [197] . In addition, IAV-specific antibody-dependent cell-mediated cytotoxicity (CDCC) also plays a role in cross-protection against IAV infection. A general description of adaptive immunity against primary IAV infection is illustrated in Figure 2 .

Antigenic shift and drift, resulting in reassorted and mutated HA and/or NA, are responsible for AIV escaping from host immunity [50] [51] [52] . Furthermore, additional glycosylation on H5 HA could also induce virus escape from neutralizing antibodies [198] .

Apoptosis represents programmed single cell death that occurs in cell physiological remodeling, cell proliferation, or immune response to invading pathogens [199] . Besides prototypical changes, cells undergoing apoptosis can be detected through DNA and biochemical assays, take the TUNEL and in situ end-labeling (ISEL) techniques for instance. Two primary pathways are involved in activation of apoptosis: the intrinsic or mitochondrial pathway, and the extrinsic or death receptor pathway.

The intrinsic pathway is also known as "the mitochondrial pathway", which operates in response to various intracellular stress. Several factors such as nitric oxide (NO), cytochrome c, and second mitochondria-derived activator of caspases (SMAC) can activate this pathway, and the key player of this pathway is proteins in the bcl-2 family, which are activated by stress signals and then release apoptotic factors via destabilizing the mitochondrial membrane [200, 201] , resulting in release of mitochondrial cytochrome c. Cytochrome c then binds to apoptosis protease activating factor-1 (APAF-1) and forms a complex with pro-caspase 9 (then cleaved into caspase 9), the function of which is to cleave its effector pro-caspase 3 [202] . In addition, SMAC, localizing in the cytosol, could initiate activation of caspase 9 via blocking the activity of IAP [203] . The extrinsic pathway is regulated by extracellular ligands acting on transmembrane "death receptors": the first apoptosis signal (FAS) receptor-FAS ligand (FASR/FASL) and the TNF-αTNF receptor 1 (TNFα/TNFR1) [199] . In the FASR/FASL model, FAS ligand binds to its receptor FASR [204] , forming the death-inducing signaling complex (DISC) with pro-caspase 8, resulting in activation of caspase 8 and downstream activation of other caspases (caspase-3, caspase-6, and caspase-7) [199] . In the TNFα/TNFR1 pathway, TNFR1-associated death domain protein (TRADD) is activated after binding of TNFα to TNFR1, leading to recruitment of FADD and receptor interacting protein (RIP) [205] . FADD then associates with pro-caspase 8 to form the DISC, resulting in activation of caspase 8 and apoptosis.

could prevent the spread of the virus from the URT to the lung [193] . To establish memory CD8 + T cells, autophagy plays an important role [194] , while the function of CD4 + T cells in memory CTL responses is "context-dependent". A recent study showed that CD4+ T cells promoted IAV-specific CTL memory at the initial priming stage of viral infection [195] . Grant and her colleagues summarized and discussed the importance of CD8 + T cell immunity against IAVs [192] , and this review is recommended for further reading.

With the help of CD40 ligand (CD40L), CD4 + cells contribute to B cell activation [183] . With the help of memory T cells, naïve B cells could reduce morbidity and promote recovery on heterosubtypic infection [196] . For different types of antibodies, IgG could inhibit pathogenesis, while IgA functions in blockin 

During IAV infection, viruses modulate host apoptotic responses in a time-dependent manner [206] . For instance, in order to earn enough time for replication and virion formation, IAV inhibited apoptosis via upregulating the anti-apoptotic phophoinositide-3-kinase-protein kinase B (PI3K-AKT) pathway at the beginning of infection. However, in the later phase of infection, the virus suppressed this pathway to upregulate the pro-apoptotic p53 pathway, thus allowing successful release of virions [207] .

Several viral proteins are involved in regulation of host apoptosis. NP protein induces host apoptosis to favor viral replication through interaction with ring finger 43 (RNF43) [208] , apoptotic inhibitor 5 (API5) [209] , or clusterin [111] . PB1-F2 also induced apoptosis and promoted viral replication through dysregulating mitochondrial potential [206] . Furthermore, M1 promoted apoptosis by binding to heat shock protein 70, thus activating caspase and the subsequent apoptosis [210] . In addition, NS1 expression was reported to induce apoptosis in MDCK and HeLa cells [211] . However, mutant IAV lacking the NS1 gene could induce apoptosis in cultured cells [212] . The function of NS1 in inhibiting apoptosis may be explained by its ability to inhibit type I IFN [213, 214] . These data demonstrate sophisticated mechanisms of IAV in regulating host apoptosis. Furthermore, the role of these viral proteins in apoptosis suggests that these proteins may present suitable targets for anti-IAV therapies. A comprehensive review on influenza A virus-induced apoptosis discussed by Ampomah and Lim is recommended here [181] . In addition, recent in vitro research found that apoptosis was induced at early IAV infection stage, while later the cell death pathway was shifted to pyroptosis. The switch process was promoted by the type I IFN-mediated JAK-STAT signaling pathway through expression of the Bcl-xL gene [215] .

During IAV infection, multiple immune systems coordinate together to protect the host. Accordingly, viruses antagonize the immune system through multiple measures to establish a successful infection. Considering the high frequencies in genome mutations and recombination, vaccination is the most effective way to defend against the viruses via inducing cross-protective antibodies and/or enhancing immune responses. Several studies in vaccine development have tried to enhance host immune responses. For instance, vaccine candidate containing HA targeted to chemokine receptor (porcine MIP1α) was shown to enhance T cell responses, resulting in a strong and cross-reactive cellular immunity in vaccinated pigs [216] . Another example is an attempt to intranasally administer a polyanhydride nano vaccine (IAV-nanovax), which could promote robust lung-resident germinal center (GC) B cells with lung-localized IAV-specific antibody responses as well as lung-resident memory CD4 + and CD8 + T cell responses [217] .

For anti-IAV drugs, currently, NA inhibitors (Relenza TM and Tamiflu TM ) are applied clinically as anti-influenza drugs [218] . These drugs inhibit the activity of NA by preventing viral budding [21] . In addition, cap-dependent endonuclease inhibitor (Baloxavir Marboxil) targeting PA is also applied against influenza A and B virus infection [219] . Our progressing understanding of the IAV life cycle of the virus and IAV-host interaction could contribute to anti-influenza drug design.

Since the recognition of HA protein to SA linked glycoproteins is the first step in IAV infection, effective blocking of the interaction between viral HA and SA receptor serves as a favorable target in drug design [220, 221] . Favipiravir, a nucleotide analogue that selectively inhibits the RNA-dependent RNA polymerase, is licensed in Japan to be applied against emerging influenza viruses resistant to other antivirals [222, 223] . Oleanolic acid (OA), a kind of pentacyclic triterpene natural product, and its analogues, as well as its derivatives, were shown to bind to HA, thus blocking the attachment of IAVs to MDCK cells [224] [225] [226] . PVF-tet is a peptide-based HA inhibitor, which was shown to sequester HA into amphisome (fusion of late endosome with autophagosome) and protected mice from the lethal IAV infection [227] .

New effective drugs targeting the polymerase would be a promising strategy against IAV infection, since they would directly reduce or eliminate viral replication. Numerous sites, including the cap-binding site [228] , the endonuclease [229, 230] , and PA-PB1 inter-subunit interface [231] can serve as potential targeting sites for new drug design. Coumarin compounds, including Eleutheroside B 1 , Isofraxidin, Fraxin, Esculetin, Fraxetin, and Scoparone, were investigated for their antiviral and anti-inflammatory activities against influenza virus in vitro [31] .

Other candidates, such as Naproxen, a non-steroidal anti-inflammatory drug, was shown to target NP protein at residues F209 and Y148, thus antagonizes the CRM1-mediated nuclear export of NP. It is suggested to have a broad-spectrum anti-influenza activity [232] . Verdinexor (KPT-335), a novel orally bioavailable drug, blocks CRM1-mediated nuclear export of NP and repress NF-κB activation, thus reducing cytokine production and eliminating virus-associated immunopathology [233] . For further reading on candidate anti-IV therapeutics, a review summarized by Davidson is recommended here [234] .

With the increasing knowledge obtained through massive investigations on host immunity against IAV infection, promoting host immune responses not limited to antibody enhancement would have good prospects not only for vaccine design, but also for development of novel antiviral agents.

Author Contributions: Manuscript preparation, Y.Z.; Revision, Z.X.; Supervision, Y.C.; Funding Acquisition, Y.Z. All authors read and approved the final version of the manuscript.

Funding: This study was supported by the "Zhujiang talent program" overseas youth talent introduction program (post-doctoral program) and Doctoral Initiative Project of Natural Science Foundation of Guangdong Province (18zxxt49).

The authors declare that they have no financial and personal relationships with other people or organizations that can influence the work. There is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in this review. They do not have any commercial or associative interest that represents conflicts of interest in connection with the work submitted.

Influenza Virus Aerosols in the Air and Their Infectiousness

Influenza: The once and future pandemic

Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus

An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response

Identification of Novel Influenza A Virus Proteins Translated from PA mRNA

Identification of a Novel Splice Variant Form of the Influenza A Virus M2 Ion Channel with an Antigenically Distinct Ectodomain

Adaptive mutation in influenza A virus non-structural gene is linked to host switching and induces a novel protein by alternative splicing

A distinct lineage of influenza A virus from bats

New World Bats Harbor Diverse Influenza A Viruses

Epidemiology, Evolution, and Pathogenesis of H7N9 Influenza Viruses in Five Epidemic Waves since 2013 in China

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses

Early Alterations of the Receptor-Binding Properties of H1, H2, and H3 Avian Influenza Virus Hemagglutinins after Their Introduction into Mammals

Influenza hemagglutinin and neuraminidase membrane glycoproteins

Receptor binding profiles of avian influenza virus hemagglutinin subtypes on human cells as a predictor of pandemic potential

Role of receptor binding specificity in influenza A virus transmission and pathogenesis

Structures and Receptor Binding of Hemagglutinins from Human-Infecting H7N9 Influenza Viruses

Avian-to-Human Receptor-Binding Adaptation of Avian H7N9 Influenza Virus Hemagglutinin

Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase

Modified sialic acids on mucus and erythrocytes inhibit influenza A HA and NA functions

Influenza neuraminidase. Influenza Other Respir

Comparative thermostability analysis of zoonotic and human influenza virus A and B neuraminidase

Neuraminidase as an influenza vaccine antigen: A low hanging fruit, ready for picking to improve vaccine effectiveness

Structural Basis of Protection against H7N9 Influenza Virus by Human Anti-N9 Neuraminidase Antibodies

Structure of influenza virus ribonucleoprotein complexes and their packaging into virions

At the centre: Influenza A virus ribonucleoproteins

Influenza virus RNA polymerase: Insights into the mechanisms of viral RNA synthesis

Human host factors required for influenza virus replication

Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication

The Nucleolar Protein LYAR Facilitates Ribonucleoprotein Assembly of Influenza A Virus

Inhibition viral RNP and anti-inflammatory activity of coumarins against influenza virus

Sequences of mRNAs derived from genome RNA segment 7 of influenza virus: Colinear and interrupted mRNAs code for overlapping proteins

Crystal Structures of Influenza A Virus Matrix Protein M1: Variations on a Theme

The M2 Proton Channels of Influenza A and B Viruses

Influenza A Virus M2 Ion Channel Activity Is Essential for Efficient Replication in Tissue Culture

The influenza A virus matrix protein 2 undergoes retrograde transport from the endoplasmic reticulum into the cytoplasm and bypasses cytoplasmic proteasomal degradation

Regulation of the extent of splicing of influenza virus NS1 mRNA: Role of the rates of splicing and of the nucleocytoplasmic transport of NS1 mRNA

Influenza A virus in vitro transcription: Roles of NS1 and NP proteins in regulating RNA synthesis

Influenza virus non-structural protein NS1: Interferon antagonism and beyond

The multifunctional NS1 protein of influenza A viruses

Recognition of viruses by cytoplasmic sensors

RIG-I Detects Viral Genomic RNA during Negative-Strand RNA Virus Infection

Structural basis for influenza virus NS1 protein block of mRNA nuclear export

Changes in RNA secondary structure affect NS1 protein expression during early stage influenza virus infection

Structure and Function of the Influenza A Virus Non-Structural Protein 1

The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins

Interaction of the Influenza Virus Nucleoprotein with the Cellular CRM1-Mediated Nuclear Export Pathway

A Second CRM1-Dependent Nuclear Export Signal in the Influenza A Virus NS2 Protein Contributes to the Nuclear Export of Viral Ribonucleoproteins

CHD3 facilitates vRNP nuclear export by interacting with NES1 of influenza A virus NS2

Investigational hemagglutinin-targeted influenza virus inhibitors

An overview of the epidemiology and emergence of influenza A infection in humans over time

Influenza vaccine: The challenge of antigenic drift

Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10

Novel insights into bat influenza A viruses

Human Infection with an Avian H9N2 Influenza A Virus in Hong Kong in 2003

Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: A descriptive study

Human Infection with a Novel Avian Influenza A (H5N6) Virus

Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus

Enabling the 'host jump': Structural determinants of receptor-binding specificity in influenza A viruses

Three mutations switch H7N9 influenza to human-type receptor specificity

Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus

Influenza A Virus Hemagglutinin-Neuraminidase-Receptor Balance: Preserving Virus Motility

Host and viral determinants of influenza A virus species specificity

History and Epidemiology of Swine Influenza in Europe

Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin

Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic

Swine Influenza (H3N2) Infection in a Child and Possible Community Transmission

Avian Influenza Virus Transmission to Mammals

Novel bioinformatics strategies for prediction of directional sequence changes in influenza virus genomes and for surveillance of potentially hazardous strains

Distinct Host Tropism Protein Signatures to Identify Possible Zoonotic Influenza A Viruses

Scoring Amino Acid Mutations to Predict Avian-to-Human Transmission of Avian Influenza Viruses

Dinucleotide Composition in Animal RNA Viruses Is Shaped More by Virus Family than by Host Species

Machine Learning Methods for Predicting Human-Adaptive Influenza A Viruses Based on Viral Nucleotide Compositions

Predicting reservoir hosts and arthropod vectors from evolutionary signatures in RNA virus genomes

Influenza A Viruses Target Type II Pneumocytes in the Human Lung

Emerging cellular targets for influenza antiviral agents

Seasonal and Pandemic Human Influenza Viruses Attach Better to Human Upper Respiratory Tract Epithelium than Avian Influenza Viruses

Human and Avian Influenza Viruses Target Different Cells in the Lower Respiratory Tract of Humans and Other Mammals

Avian influenza and sialic acid receptors: More than meets the eye?

Influenza A virus entry into cells lacking sialylated N-glycans

Avian influenza among waterfowl hunters and wildlife professionals

TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections

Cleavage Activation of the Human-Adapted Influenza Virus Subtypes by Matriptase Reveals both Subtype and Strain Specificities

A Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus

Proteolytic Activation of the 1918 Influenza Virus Hemagglutinin

From low to high pathogenicity-Characterization of H7N7 avian influenza viruses in two epidemiologically linked outbreaks

Subtype-specific structural constraints in the evolution of influenza A virus hemagglutinin genes

Nuclear traffic of influenza virus proteins and ribonucleoprotein complexes

The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit

Mutations of the segment-specific nucleotides at the 3 end of influenza virus NS segment control viral replication

The tyrosine 73 and serine 83 dephosphorylation of H1N1 swine influenza virus NS1 protein attenuates virus replication and induces high levels of beta interferon

Crystal structure of the M1 protein-binding domain of the influenza A virus nuclear export protein (NEP/NS2)

N-Linked Glycosylation of the Hemagglutinin Protein Influences Virulence and Antigenicity of the 1918 Pandemic and Seasonal H1N1 Influenza A Viruses

Site-specific S-acylation of influenza virus hemagglutinin: the location of the acylation site relative to the membrane border is the decisive factor for attachment of stearate

Influenza A Virus Hemagglutinin and Neuraminidase Mutually Accelerate Their Apical Targeting through Clustering of Lipid Rafts

Apical Trafficking Pathways of Influenza A Virus HA and NA via Rab17-and Rab23-Positive Compartments

A Rab11-and Microtubule-Dependent Mechanism for Cytoplasmic Transport of Influenza A Virus Viral RNA

Influenza virus assembly and budding

Characterization of temperature sensitive influenza virus mutants defective in neuraminidase

Uncovering the global host cell requirements for influenza virus replication via RNAi screening. Microbes Infect

Knockdown of specific host factors protects against influenza virus-induced cell death

Genome-wide CRISPR/Cas9 Screen Identifies Host Factors Essential for Influenza Virus Replication

Genome-wide CRISPR screen identifies host dependency factors for influenza A virus infection

Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection

Innate immunity to influenza virus infection

Innate immune evasion strategies of influenza viruses

The Role of IL-10 in Regulating Immunity to Persistent Viral Infections

Formyl peptide receptor 2 is regulated by RNA mimics and viruses through an IFN-β-STAT3-dependent pathway

Influenza A virus enhances its propagation through the modulation of Annexin-A1 dependent endosomal trafficking and apoptosis

Influenza Virus Induces Apoptosis via BAD-Mediated Mitochondrial Dysregulation

Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: Implications of a novel interaction between nucleoprotein and host protein Clusterin

Autophagy induction regulates influenza virus replication in a time-dependent manner

Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus

Modulation of Innate Immune Responses by the Influenza A NS1 and PA-X Proteins

Host Immune Response to Influenza A Virus Infection

NKp46 O-Glycan Sequences That Are Involved in the Interaction with Hemagglutinin Type 1 of Influenza Virus

Evasion of natural killer cells by influenza virus

Respiratory Influenza Virus Infection Induces Memory-like Liver NK Cells in Mice

Critical Role of Natural Killer Cells in Lung Immunopathology During Influenza Infection in Mice

NK cells exacerbate the pathology of influenza virus infection in mice

Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

A Role for Neutrophils in Viral Respiratory Disease. Front. Immunol. 2017, 8, 550

Neutrophil trails guide influenza-specific CD8+ T cells in the airways

Clearance of influenza virus from the lung depends on migratory langerin+CD11b-but not plasmacytoid dendritic cells

Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node

Activation of Dendritic Cells Alters the Mechanism of MHC Class II Antigen Presentation to CD4 T Cells

Dendritic cells and influenza A virus infection

Toll-Like Receptor Adaptor Molecules Enhance DNA-Raised Adaptive Immune Responses against Influenza and Tumors through Activation of Innate Immunity

Toll-like receptor 3 promotes cross-priming to virus-infected cells

Cutting Edge: Influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells

A Single-Stranded Oligonucleotide Inhibits Toll-Like Receptor 3 Activation and Reduces Influenza A (H1N1)

Recognition of single-stranded RNA viruses by Toll-like receptor 7

Antiviral response elicited against avian influenza virus infection following activation of toll-like receptor (TLR)7 signaling pathway is attributable to interleukin (IL)-1β production

Respiratory Influenza A Virus Infection Triggers Local and Systemic Natural Killer Cell Activation via Toll-Like Receptor 7

TLR7 Recognition Is Dispensable for Influenza Virus A Infection but Important for the Induction of Hemagglutinin-Specific Antibodies in Response to the 2009 Pandemic Split Vaccine in Mice

Toll-like Receptor 7 Is Required for Effective Adaptive Immune Responses that Prevent Persistent Virus Infection

Viral RNA detection by RIG-I-like receptors

OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1

RIG-I-mediated antiviral responses to single-stranded RNA bearing 5 -phosphates

NOD proteins: Regulators of inflammation in health and disease

Influenza virus activates inflammasomes via its intracellular M2 ion channel

Activation of the NLRP3 Inflammasome by IAV Virulence Protein PB1-F2 Contributes to Severe Pathophysiology and Disease

The role of the NLRP3 inflammasome in regulation of antiviral responses to influenza A virus infection

Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration

Interferons and viruses: An interplay between induction, signalling, antiviral responses and virus countermeasures

Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses

Interferon-stimulated genes: A complex web of host defenses

Type I and Type III Interferons Drive Redundant Amplification Loops to Induce a Transcriptional Signature in Influenza-Infected Airway Epithelia

Interferon-λ Mediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness

Interferon-λ modulates dendritic cells to facilitate T cell immunity during infection with influenza A virus

The human interferon-induced MxA protein inhibits early stages of influenza A virus infection by retaining the incoming viral genome in the cytoplasm

Pandemic Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein

25-Hydroxycholesterol acts as an amplifier of inflammatory signaling

A new splice variant of the human guanylate-binding protein 3 mediates anti-influenza activity through inhibition of viral transcription and replication

Inhibition of Influenza A Virus Replication by TRIM14 via Its Multifaceted Protein-Protein Interaction with

TRIM22 Inhibits Influenza A Virus Infection by Targeting the Viral Nucleoprotein for Degradation

TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity

TRIM32 Senses and Restricts Influenza A Virus by Ubiquitination of PB1 Polymerase

TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection

Influenza Virus Infection, Interferon Response, Viral Counter-Response, and Apoptosis

Influenza virus activation of the interferon system

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor

A novel influenza A virus mitochondrial protein that induces cell death

Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon by Binding to MAVS and Decreasing Mitochondrial Membrane Potential

Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza

Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy

Nutrient-dependent mTORC1 Association with the ULK1-Atg13-FIP200 Complex Required for Autophagy

Connecting endoplasmic reticulum stress to autophagy through IRE1/JNK/beclin-1 in breast cancer cells

Reactive Oxygen Species-Mediated c-Jun NH2-Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells

The Regulation of Autophagy by Influenza A Virus

TRIM23 mediates virus-induced autophagy via activation of TBK1

Influenza A Virus NS1 Protein Suppresses JNK1-Dependent Autophagosome Formation Mediated by Rab11a Recycling Endosomes

Role of TGF-β-activated kinase 1 (TAK1) activation in H5N1 influenza A virus-induced c-Jun terminal kinase activation and virus replication

Essential role for autophagy in the maintenance of immunological memory against influenza infection

Matrix Protein 2 of Influenza A Virus Blocks Autophagosome Fusion with Lysosomes

A LIR motif in influenza A virus M2 is required for virion stability

Proton Channel Activity of Influenza A Virus Matrix Protein 2 Contributes to Autophagy Arrest

Circular RNA GATAD2A promotes H1N1 replication through inhibiting autophagy

Influenza A virus-induced apoptosis and virus propagation

Antigen-specific and non-specific CD4+ T cell recruitment and proliferation during influenza infection

Expanding roles for CD4+ T cells in immunity to viruses

IL-17-Induced Pulmonary Pathogenesis during Respiratory Viral Infection and Exacerbation of Allergic Disease

Imbalanced pro-and anti-Th17 responses (IL-17/granulocyte colony-stimulating factor) predict fatal outcome in 2009 pandemic influenza

Ketogenic diet activates protective γδ T cell responses against influenza virus infection

Kinetics and Phenotype of the CD4 T Cell Response to Influenza Virus Infections

T cell mediated immunity to influenza: Mechanisms of viral control

Non-cytotoxic antiviral activities of granzymes in the context of the immune antiviral state

Pulmonary immunity to viruses

IL16 deficiency enhances Th1 and cytotoxic T lymphocyte response against influenza A virus infection

Human influenza viruses and CD8 + T cell responses

Resident memory CD8+T cells in the upper respiratory tract prevent pulmonary influenza virus infection

Autophagy is a critical regulator of memory CD8+ T cell formation

CD4+T help promotes influenza virus-specific CD8+T cell memory by limiting metabolic dysfunction

B cells promote resistance to heterosubtypic strains of influenza via multiple mechanisms1

Recombinant IgA Is Sufficient To Prevent Influenza Virus Transmission in Guinea Pigs

Addition of N-glycosylation sites on the globular head of the H5 hemagglutinin induces the escape of highly pathogenic avian influenza A H5N1 viruses from vaccine-induced immunity

Apoptosis: A Review of Programmed Cell Death

Bcl-2 Gene Family in Endocrine Pathology: A Review

Nitric oxide: NO apoptosis or turning it ON?

Promotion of Caspase Activation by Caspase-9-mediated Feedback Amplification of Mitochondrial Damage

Smac, a Mitochondrial Protein that Promotes Cytochrome c-Dependent Caspase Activation by Eliminating IAP Inhibition

The Many Roles of FAS Receptor Signaling in the Immune System

The Fas Signaling Pathway: More Than a Paradigm

Viral Control of Mitochondrial Apoptosis

Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling

The nucleoprotein of influenza A virus induces p53 signaling and apoptosis via attenuation of host ubiquitin ligase RNF43

Nucleoprotein of influenza A virus negatively impacts antiapoptotic protein API5 to enhance E2F1-dependent apoptosis and virus replication

Cell death regulation during influenza A virus infection by matrix (M1) protein: A model of viral control over the cellular survival pathway

Influenza Virus NS1 Protein Induces Apoptosis in Cultured Cells

Loss of function of the influenza A virus NS1 protein promotes apoptosis but this is not due to a failure to activate phosphatidylinositol 3-kinase (PI3K)

Pathogenic potential of interferon αβ in acute influenza infection

IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment

Influenza A Virus Infection Triggers Pyroptosis and Apoptosis of Respiratory Epithelial Cells through the Type I Interferon Signaling Pathway in a Mutually Exclusive Manner

Targeting of HA to chemokine receptors induces strong and cross-reactive T cell responses after DNA vaccination in pigs

Polyanhydride Nanovaccine Induces Robust Pulmonary B and T Cell Immunity and Confers Protection Against Homologous and Heterologous Influenza A Virus Infections

Influenza neuraminidase inhibitors: Antiviral action and mechanisms of resistance. Influenza Other Respir. Viruses

Baloxavir marboxil: The new influenza drug on the market

Emerging Antiviral Strategies to Interfere with Influenza Virus Entry

Discovery of the First Series of Small Molecule H5N1 Entry Inhibitors

Favipiravir (T-705), a novel viral RNA polymerase inhibitor

Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase

Synthesis, Structure Activity Relationship and Anti-influenza A Virus Evaluation of Oleanolic Acid-Linear Amino Derivatives

Design, synthesis of oleanolic acid-saccharide conjugates using click chemistry methodology and study of their anti-influenza activity

Design, synthesis and biological evaluation of amino acids-oleanolic acid conjugates as influenza virus inhibitors

The inducible amphisome isolates viral hemagglutinin and defends against influenza A virus infection

Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2

A Novel Endonuclease Inhibitor Exhibits Broad-Spectrum Anti-Influenza Virus ActivityIn Vitro

Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor

Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Protein-Protein Interaction as a Target for Next-Generation Anti-influenza Therapeutics

Naproxen Exhibits Broad Anti-influenza Virus Activity in Mice by Impeding Viral Nucleoprotein Nuclear Export

Verdinexor Targeting of CRM1 is a Promising Therapeutic Approach against RSV and Influenza Viruses

Treating Influenza Infection, From Now and Into the Future