Influenza A viruses (IAVs) cause mild to severe infections in humans with considerable socioeconomic and global health consequences. The host interferon (IFN)-α/β response, critical as the first line of defense against foreign pathogens, is induced upon detection of IAV genomic RNA in infected cells by host innate pattern recognition receptors. IFN-α/β production and subsequent activation of cell signaling result in the expression of antiviral IFN-stimulated genes whose products target various stages of the IAV life cycle to inhibit viral replication and the spread of infection and establish an antiviral state. IAVs, however, encode a multifunctional virulence factor, nonstructural protein 1 (NS1), that directly antagonizes the host IFN-α/β response to support viral replication. In this review, we highlight the mechanisms by which NS1 suppresses IFN-α/β production and subsequent cell signaling, and consider, therefore, the potential for recombinant IAVs lacking NS1 to be used as live-attenuated vaccines.
Get full access to this article
View all access options for this article.
References
1.
AbdoliA, SoleimanjahiH, Tavassoti KheiriM, JamaliA, JamaatiA. 2013. Determining influenza virus shedding at different time points in madin-darby canine kidney cell line. Cell J, 15(2):130–135.
2.
AblasserA, PoeckH, AnzD, BergerM, SchleeM, KimS, BourquinC, GoutagnyN, JiangZ, FitzgeraldKA, RothenfusserS, EndresS, HartmannG, HornungV. 2009. Selection of molecular structure and delivery of RNA oligonucleotides to activate TLR7 versus TLR8 and to induce high amounts of IL-12p70 in primary human monocytes. J Immunol, 182(11):6824–6833.
3.
AllenIC, ScullMA, MooreCB, HollEK, McElvania-TeKippeE, TaxmanDJ, GuthrieEH, PicklesRJ, TingJP. 2009. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity, 30(4):556–565.
4.
ArimoriY, NakamuraR, YamadaH, ShibataK, MaedaN, KaseT, YoshikaiY. 2013. Type I interferon limits influenza virus-induced acute lung injury by regulation of excessive inflammation in mice. Antiviral Res, 99(3):230–237.
5.
AyllonJ, HaleBG, Garcia-SastreA. 2012. Strain-specific contribution of NS1-activated phosphoinositide 3-kinase signaling to influenza A virus replication and virulence. J Virol, 86(9):5366–5370.
6.
BeanB, MooreBM, SternerB, PetersonLR, GerdingDN, BalfourHHJr. 1982. Survival of influenza viruses on environmental surfaces. J Infect Dis, 146(1):47–51.
7.
BenitezAA, PanisM, XueJ, VarbleA, ShimJV, FrickAL, LopezCB, SachsD, tenOeverBR. 2015. In vivo RNAi screening identifies MDA5 as a significant contributor to the cellular defense against influenza A virus. Cell Rep, 11(11):1714–1726.
8.
BennettAL, SmithDW, CumminsMJ, JacobyPA, CumminsJM, BeilharzMW. 2013. Low-dose oral interferon alpha as prophylaxis against viral respiratory illness: a double-blind, parallel controlled trial during an influenza pandemic year. Influenza Other Respir Viruses, 7(5):854–862.
9.
BergmannM, Garcia-SastreA, CarneroE, PehambergerH, WolffK, PaleseP, MusterT. 2000. Influenza virus NS1 protein counteracts PKR-mediated inhibition of replication. J Virol, 74(13):6203–6206.
10.
BhardwajN, BenderA, GonzalezN, BuiLK, GarrettMC, SteinmanRM. 1994. Influenza virus-infected dendritic cells stimulate strong proliferative and cytolytic responses from human CD8+ T cells. J Clin Invest, 94(2):797–807.
11.
BrassAL, HuangIC, BenitaY, JohnSP, KrishnanMN, FeeleyEM, RyanBJ, WeyerJL, van der WeydenL, FikrigE, AdamsDJ, XavierRJ, FarzanM, ElledgeSJ. 2009. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell, 139(7):1243–1254.
12.
ChakrabartiA, BanerjeeS, FranchiL, LooYM, GaleMJr., NunezG, SilvermanRH. 2015. RNase L activates the NLRP3 inflammasome during viral infections. Cell Host Microbe, 17(4):466–477.
13.
ChebathJ, BenechP, HovanessianA, GalabruJ, RevelM. 1987. Four different forms of interferon-induced 2',5'-oligo(A) synthetase identified by immunoblotting in human cells. J Biol Chem, 262(8):3852–3857.
14.
CooperDA, BanerjeeS, ChakrabartiA, Garcia-SastreA, HesselberthJR, SilvermanRH, BartonDJ. 2015. RNase L targets distinct sites in influenza A virus RNAs. J Virol, 89(5):2764–2776.
15.
DarapaneniV, PrabhakerVK, KukolA. 2009. Large-scale analysis of influenza A virus sequences reveals potential drug target sites of non-structural proteins. J Gen Virol, 90(Pt 9):2124–2133.
16.
DasK, MaLC, XiaoR, RadvanskyB, AraminiJ, ZhaoL, MarklundJ, KuoRL, TwuKY, ArnoldE, KrugRM, MontelioneGT. 2008. Structural basis for suppression of a host antiviral response by influenza A virus. Proc Natl Acad Sci U S A, 105(35):13093–13098.
17.
DawoodFS, JainS, FinelliL, ShawMW, LindstromS, GartenRJ, GubarevaLV, XuX, BridgesCB, UyekiTM. 2009. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med, 360(25):2605–2615.
18.
de JongMD, SimmonsCP, ThanhTT, HienVM, SmithGJ, ChauTN, HoangDM, ChauNV, KhanhTH, DongVC, QuiPT, CamBV, Ha doQ, GuanY, PeirisJS, ChinhNT, HienTT, FarrarJ. 2006. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med, 12(10):1203–1207.
19.
DesaiTM, MarinM, ChinCR, SavidisG, BrassAL, MelikyanGB. 2014. IFITM3 restricts influenza A virus entry by blocking the formation of fusion pores following virus-endosome hemifusion. PLoS Pathog, 10(4):e1004048.
20.
DieboldSS, KaishoT, HemmiH, AkiraS, Reis e SousaC. 2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science, 303(5663):1529–1531.
21.
DonovanJ, WhitneyG, RathS, KorennykhA. 2015. Structural mechanism of sensing long dsRNA via a noncatalytic domain in human oligoadenylate synthetase 3. Proc Natl Acad Sci U S A, 112(13):3949–3954.
22.
FalconAM, Fernandez-SesmaA, NakayaY, MoranTM, OrtinJ, Garcia-SastreA. 2005. Attenuation and immunogenicity in mice of temperature-sensitive influenza viruses expressing truncated NS1 proteins. J Gen Virol, 86(Pt 10):2817–2821.
23.
FerkoB, StasakovaJ, RomanovaJ, KittelC, SereinigS, KatingerH, EgorovA. 2004. Immunogenicity and protection efficacy of replication-deficient influenza A viruses with altered NS1 genes. J Virol, 78(23):13037–13045.
24.
Floyd-SmithG, SlatteryE, LengyelP. 1981. Interferon action: RNA cleavage pattern of a (2'-5')oligoadenylate—dependent endonuclease. Science, 212(4498):1030–1032.
25.
FouchierRA, SchneebergerPM, RozendaalFW, BroekmanJM, KeminkSA, MunsterV, KuikenT, RimmelzwaanGF, SchuttenM, Van DoornumGJ, KochG, BosmanA, KoopmansM, OsterhausAD. 2004. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A, 101(5):1356–1361.
26.
GackMU, AlbrechtRA, UranoT, InnKS, HuangIC, CarneroE, FarzanM, InoueS, JungJU, Garcia-SastreA. 2009. Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe, 5(5):439–449.
27.
GaoL, YuS, ChenQ, DuanZ, ZhouJ, MaoC, YuD, ZhuW, NieJ, HouY. 2010. A randomized controlled trial of low-dose recombinant human interferons alpha-2b nasal spray to prevent acute viral respiratory infections in military recruits. Vaccine, 28(28):4445–4451.
28.
Garcia-SastreA, DurbinRK, ZhengH, PaleseP, GertnerR, LevyDE, DurbinJE. 1998a. The role of interferon in influenza virus tissue tropism. J Virol, 72(11):8550–8558.
29.
Garcia-SastreA, EgorovA, MatassovD, BrandtS, LevyDE, DurbinJE, PaleseP, MusterT. 1998b. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology, 252(2):324–330.
30.
GuillotL, Le GofficR, BlochS, EscriouN, AkiraS, ChignardM, Si-TaharM. 2005. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. J Biol Chem, 280(7):5571–5580.
31.
HatadaE, SaitoS, FukudaR. 1999. Mutant influenza viruses with a defective NS1 protein cannot block the activation of PKR in infected cells. J Virol, 73(3):2425–2433.
32.
HayeK, BurmakinaS, MoranT, Garcia-SastreA, Fernandez-SesmaA. 2009. The NS1 protein of a human influenza virus inhibits type I interferon production and the induction of antiviral responses in primary human dendritic and respiratory epithelial cells. J Virol, 83(13):6849–6862.
33.
HeerAK, ShamshievA, DondaA, UematsuS, AkiraS, KopfM, MarslandBJ. 2007. TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses. J Immunol, 178(4):2182–2191.
34.
HovanessianAG, SvabJ, MarieI, RobertN, ChamaretS, LaurentAG. 1988. Characterization of 69- and 100-kDa forms of 2-5A-synthetase from interferon-treated human cells. J Biol Chem, 263(10):4945–4949.
35.
HsiangTY, ZhaoC, KrugRM. 2009. Interferon-induced ISG15 conjugation inhibits influenza A virus gene expression and replication in human cells. J Virol, 83(12):5971–5977.
36.
HuangIC, BaileyCC, WeyerJL, RadoshitzkySR, BeckerMM, ChiangJJ, BrassAL, AhmedAA, ChiX, DongL, LongobardiLE, BoltzD, KuhnJH, ElledgeSJ, BavariS, DenisonMR, ChoeH, FarzanM. 2011. Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS Pathog, 7(1):e1001258.
37.
IchinoheT, PangIK, IwasakiA. 2010. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat Immunol, 11(5):404–410.
38.
JewellNA, VaghefiN, MertzSE, AkterP, PeeblesRSJr., BakaletzLO, DurbinRK, FlanoE, DurbinJE. 2007. Differential type I interferon induction by respiratory syncytial virus and influenza a virus in vivo. J Virol, 81(18):9790–9800.
JurekaAS, KleinpeterAB, CornilescuG, CornilescuCC, PetitCM. 2015. Structural basis for a novel interaction between the NS1 protein derived from the 1918 influenza virus and RIG-I. Structure, 23(11):2001–2010.
41.
KatoH, TakeuchiO, SatoS, YoneyamaM, YamamotoM, MatsuiK, UematsuS, JungA, KawaiT, IshiiKJ, YamaguchiO, OtsuK, TsujimuraT, KohCS, Reis e SousaC, MatsuuraY, FujitaT, AkiraS. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature, 441(7089):101–105.
42.
KleinMB, LuY, DelBalsoL, CoteS, BoivinG. 2007. Influenzavirus infection is a primary cause of febrile respiratory illness in HIV-infected adults, despite vaccination. Clin Infect Dis, 45(2):234–240.
43.
KochsG, Garcia-SastreA, Martinez-SobridoL. 2007. Multiple anti-interferon actions of the influenza A virus NS1 protein. J Virol, 81(13):7011–7021.
44.
KochsG, Martinez-SobridoL, LienenklausS, WeissS, Garcia-SastreA, StaeheliP. 2009. Strong interferon-inducing capacity of a highly virulent variant of influenza A virus strain PR8 with deletions in the NS1 gene. J Gen Virol, 90(Pt 12):2990–2994.
45.
KochsG, ReicheltM, DaninoD, HinshawJE, HallerO. 2005. Assay and functional analysis of dynamin-like Mx proteins. Methods Enzymol, 404:632–643.
46.
KoernerI, KochsG, KalinkeU, WeissS, StaeheliP. 2007. Protective role of beta interferon in host defense against influenza A virus. J Virol, 81(4):2025–2030.
47.
KoyamaS, IshiiKJ, KumarH, TanimotoT, CobanC, UematsuS, KawaiT, AkiraS. 2007. Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J Immunol, 179(7):4711–4720.
48.
KugelD, KochsG, ObojesK, RothJ, KobingerGP, KobasaD, HallerO, StaeheliP, von MesslingV. 2009. Intranasal administration of alpha interferon reduces seasonal influenza A virus morbidity in ferrets. J Virol, 83(8):3843–3851.
49.
Le GofficR, BalloyV, LagranderieM, AlexopoulouL, EscriouN, FlavellR, ChignardM, Si-TaharM. 2006. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog, 2(6):e53.
50.
Le GofficR, PothlichetJ, VitourD, FujitaT, MeursE, ChignardM, Si-TaharM. 2007. Cutting Edge: influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J Immunol, 178(6):3368–3372.
51.
LenschowDJ, LaiC, Frias-StaheliN, GiannakopoulosNV, LutzA, WolffT, OsiakA, LevineB, SchmidtRE, Garcia-SastreA, LeibDA, PekoszA, KnobelochKP, HorakI, VirginHWt. 2007. IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc Natl Acad Sci U S A, 104(4):1371–1376.
52.
LiG, XiangY, SabapathyK, SilvermanRH. 2004. An apoptotic signaling pathway in the interferon antiviral response mediated by RNase L and c-Jun NH2-terminal kinase. J Biol Chem, 279(2):1123–1131.
53.
LiS, MinJY, KrugRM, SenGC. 2006a. Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology, 349(1):13–21.
54.
LiS, PetersGA, DingK, ZhangX, QinJ, SenGC. 2006b. Molecular basis for PKR activation by PACT or dsRNA. Proc Natl Acad Sci U S A, 103(26):10005–10010.
55.
LinigerM, SummerfieldA, ZimmerG, McCulloughKC, RuggliN. 2012. Chicken cells sense influenza A virus infection through MDA5 and CARDIF signaling involving LGP2. J Virol, 86(2):705–717.
56.
LoebKR, HaasAL. 1992. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem, 267(11):7806–7813.
57.
LooYM, FornekJ, CrochetN, BajwaG, PerwitasariO, Martinez-SobridoL, AkiraS, GillMA, Garcia-SastreA, KatzeMG, GaleMJr. 2008. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol, 82(1):335–345.
58.
LudwigS, WangX, EhrhardtC, ZhengH, DonelanN, PlanzO, PleschkaS, Garcia-SastreA, HeinsG, WolffT. 2002. The influenza A virus NS1 protein inhibits activation of Jun N-terminal kinase and AP-1 transcription factors. J Virol, 76(21):11166–11171.
59.
LupferC, ThomasPG, KannegantiTD. 2014. Nucleotide oligomerization and binding domain 2-dependent dendritic cell activation is necessary for innate immunity and optimal CD8+ T cell responses to influenza A virus infection. J Virol, 88(16):8946–8955.
60.
MalakhovaOA, YanM, MalakhovMP, YuanY, RitchieKJ, KimKI, PetersonLF, ShuaiK, ZhangDE. 2003. Protein ISGylation modulates the JAK-STAT signaling pathway. Genes Dev, 17(4):455–460.
61.
MalathiK, DongB, GaleMJr., SilvermanRH. 2007. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature, 448(7155):816–819.
62.
ManicassamyB, ManicassamyS, Belicha-VillanuevaA, PisanelliG, PulendranB, Garcia-SastreA. 2010. Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus. Proc Natl Acad Sci U S A, 107(25):11531–11536.
63.
MelenK, KinnunenL, FagerlundR, IkonenN, TwuKY, KrugRM, JulkunenI. 2007. Nuclear and nucleolar targeting of influenza A virus NS1 protein: striking differences between different virus subtypes. J Virol, 81(11):5995–6006.
64.
MibayashiM, Martinez-SobridoL, LooYM, CardenasWB, GaleMJr., Garcia-SastreA. 2007. Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol, 81(2):514–524.
65.
MinJY, KrugRM. 2006. The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: inhibiting the 2'-5' oligo (A) synthetase/RNase L pathway. Proc Natl Acad Sci U S A, 103(18):7100–7105.
66.
MinJY, LiS, SenGC, KrugRM. 2007. A site on the influenza A virus NS1 protein mediates both inhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology, 363(1):236–243.
67.
MolinariNA, Ortega-SanchezIR, MessonnierML, ThompsonWW, WortleyPM, WeintraubE, BridgesCB. 2007. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine, 25(27):5086–5096.
68.
MordsteinM, KochsG, DumoutierL, RenauldJC, PaludanSR, KlucherK, StaeheliP. 2008. Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog, 4(9):e1000151.
69.
NiggPE, PavlovicJ. 2015. Oligomerization and GTP-binding Requirements of MxA for viral target recognition and antiviral activity against influenza A virus. J Biol Chem, 290(50):29893–29906.
70.
NotiJD, LindsleyWG, BlachereFM, CaoG, KashonML, ThewlisRE, McMillenCM, KingWP, SzalajdaJV, BeezholdDH. 2012. Detection of infectious influenza virus in cough aerosols generated in a simulated patient examination room. Clin Infect Dis, 54(11):1569–1577.
71.
OnomotoK, JogiM, YooJS, NaritaR, MorimotoS, TakemuraA, SambharaS, KawaguchiA, OsariS, NagataK, MatsumiyaT, NamikiH, YoneyamaM, FujitaT. 2012. Critical role of an antiviral stress granule containing RIG-I and PKR in viral detection and innate immunity. PLoS One, 7(8):e43031.
72.
PauliEK, SchmolkeM, WolffT, ViemannD, RothJ, BodeJG, LudwigS. 2008. Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression. PLoS Pathog, 4(11):e1000196.
73.
PeirisJS, YuWC, LeungCW, CheungCY, NgWF, NichollsJM, NgTK, ChanKH, LaiST, LimWL, YuenKY, GuanY. 2004. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet, 363(9409):617–619.
74.
PichlmairA, SchulzO, TanCP, NaslundTI, LiljestromP, WeberF, Reis e SousaC. 2006. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science, 314(5801):997–1001.
75.
PirhonenJ, SarenevaT, KurimotoM, JulkunenI, MatikainenS. 1999. Virus infection activates IL-1 beta and IL-18 production in human macrophages by a caspase-1-dependent pathway. J Immunol, 162(12):7322–7329.
76.
RajsbaumR, AlbrechtRA, WangMK, MaharajNP, VersteegGA, Nistal-VillanE, Garcia-SastreA, GackMU. 2012. Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein. PLoS Pathog, 8(11):e1003059.
77.
RamosI, CarneroE, Bernal-RubioD, SeibertCW, WesteraL, Garcia-SastreA, Fernandez-SesmaA. 2013. Contribution of double-stranded RNA and CPSF30 binding domains of influenza virus NS1 to the inhibition of type I interferon production and activation of human dendritic cells. J Virol, 87(5):2430–2440.
78.
RohaniP, BrebanR, StallknechtDE, DrakeJM. 2009. Environmental transmission of low pathogenicity avian influenza viruses and its implications for pathogen invasion. Proc Natl Acad Sci U S A, 106(25):10365–10369.
79.
RuckleA, HaasbachE, JulkunenI, PlanzO, EhrhardtC, LudwigS. 2012. The NS1 protein of influenza A virus blocks RIG-I-mediated activation of the noncanonical NF-kappaB pathway and p52/RelB-dependent gene expression in lung epithelial cells. J Virol, 86(18):10211–10217.
80.
RuschL, ZhouA, SilvermanRH. 2000. Caspase-dependent apoptosis by 2',5'-oligoadenylate activation of RNase L is enhanced by IFN-beta. J Interferon Cytokine Res, 20(12):1091–1100.
SabbahA, ChangTH, HarnackR, FrohlichV, TominagaK, DubePH, XiangY, BoseS. 2009. Activation of innate immune antiviral responses by Nod2. Nat Immunol, 10(10):1073–1080.
83.
SeoSU, KwonHJ, KoHJ, ByunYH, SeongBL, UematsuS, AkiraS, KweonMN. 2011. Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice. PLoS Pathog, 7(2):e1001304.
84.
ShapiroGI, GurneyTJr., KrugRM. 1987. Influenza virus gene expression: control mechanisms at early and late times of infection and nuclear-cytoplasmic transport of virus-specific RNAs. J Virol, 61(3):764–773.
85.
ShiHX, YangK, LiuX, LiuXY, WeiB, ShanYF, ZhuLH, WangC. 2010. Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification. Mol Cell Biol, 30(10):2424–2436.
86.
ShinDL, HatesuerB, BergmannS, NedelkoT, SchughartK. 2015. Protection from severe influenza virus infections in mice carrying the Mx1 influenza virus resistance gene strongly depends on genetic background. J Virol, 89(19):9998–10009.
87.
ShindeV, BridgesCB, UyekiTM, ShuB, BalishA, XuX, LindstromS, GubarevaLV, DeydeV, GartenRJ, HarrisM, GerberS, VagaskyS, SmithF, PascoeN, MartinK, DufficyD, RitgerK, ConoverC, QuinliskP, KlimovA, BreseeJS, FinelliL. 2009. Triple-reassortant swine influenza A (H1) in humans in the United States, 2005–2009. N Engl J Med, 360(25):2616–2625.
88.
StaeheliP, GrobR, MeierE, SutcliffeJG, HallerO. 1988. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Mol Cell Biol, 8(10):4518–4523.
89.
SzretterKJ, GangappaS, BelserJA, ZengH, ChenH, MatsuokaY, SambharaS, SwayneDE, TumpeyTM, KatzJM. 2009. Early control of H5N1 influenza virus replication by the type I interferon response in mice. J Virol, 83(11):5825–5834.
90.
TalonJ, SalvatoreM, O'NeillRE, NakayaY, ZhengH, MusterT, Garcia-SastreA, PaleseP. 2000. Influenza A and B viruses expressing altered NS1 proteins: a vaccine approach. Proc Natl Acad Sci U S A, 97(8):4309–4314.
91.
TateMD, PickettDL, van RooijenN, BrooksAG, ReadingPC. 2010. Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J Virol, 84(15):7569–7580.
92.
TeijaroJR, WalshKB, CahalanS, FremgenDM, RobertsE, ScottF, MartinboroughE, PeachR, OldstoneMB, RosenH. 2011. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell, 146(6):980–991.
93.
ThompsonWW, ShayDK, WeintraubE, BrammerL, CoxN, AndersonLJ, FukudaK. 2003. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA, 289(2):179–186.
94.
TumpeyTM, SzretterKJ, Van HoevenN, KatzJM, KochsG, HallerO, Garcia-SastreA, StaeheliP. 2007. The Mx1 gene protects mice against the pandemic 1918 and highly lethal human H5N1 influenza viruses. J Virol, 81(19):10818–10821.
95.
TwuKY, NoahDL, RaoP, KuoRL, KrugRM. 2006. The CPSF30 binding site on the NS1A protein of influenza A virus is a potential antiviral target. J Virol, 80(8):3957–3965.
96.
UetaniK, HiroiM, MeguroT, OgawaH, KamisakoT, OhmoriY, ErzurumSC. 2008. Influenza A virus abrogates IFN-gamma response in respiratory epithelial cells by disruption of the Jak/Stat pathway. Eur J Immunol, 38(6):1559–1573.
97.
VerhelstJ, ParthoensE, SchepensB, FiersW, SaelensX. 2012. Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly. J Virol, 86(24):13445–13455.
98.
VilchezRA, McCurryK, DauberJ, LaconoA, GriffithB, FungJ, KusneS. 2002. Influenza virus infection in adult solid organ transplant recipients. Am J Transplant, 2(3):287–291.
99.
WacheckV, EgorovA, GroissF, PfeifferA, FuerederT, HoeflmayerD, KundiM, Popow-KrauppT, Redlberger-FritzM, MuellerCA, CinatlJ, MichaelisM, GeilerJ, BergmannM, RomanovaJ, RoethlE, MorokuttiA, WolschekM, FerkoB, SeipeltJ, Dick-GudenusR, MusterT. 2010. A novel type of influenza vaccine: safety and immunogenicity of replication-deficient influenza virus created by deletion of the interferon antagonist NS1. J Infect Dis, 201(3):354–362.
100.
WangJ, NikradMP, TravantyEA, ZhouB, PhangT, GaoB, AlfordT, ItoY, NahreiniP, HartshornK, WentworthD, DinarelloCA, MasonRJ. 2012. Innate immune response of human alveolar macrophages during influenza A infection. PLoS One, 7(3):e29879.
101.
WangJP, BowenGN, PaddenC, CernyA, FinbergRW, NewburgerPE, Kurt-JonesEA. 2008. Toll-like receptor-mediated activation of neutrophils by influenza A virus. Blood, 112(5):2028–2034.
102.
WangX, HinsonER, CresswellP. 2007. The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts. Cell Host Microbe, 2(2):96–105.
103.
WangX, LiM, ZhengH, MusterT, PaleseP, BegAA, Garcia-SastreA. 2000. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon. J Virol, 74(24):11566–11573.
104.
WeiL, CuiJ, SongY, ZhangS, HanF, YuanR, GongL, JiaoP, LiaoM. 2014. Duck MDA5 functions in innate immunity against H5N1 highly pathogenic avian influenza virus infections. Vet Res, 45:66.
WreschnerDH, JamesTC, SilvermanRH, KerrIM. 1981. Ribosomal RNA cleavage, nuclease activation and 2-5A(ppp(A2'p)nA) in interferon-treated cells. Nucleic Acids Res, 9(7):1571–1581.
107.
YangX, ChangHY, BaltimoreD. 1998. Autoproteolytic activation of pro-caspases by oligomerization. Mol Cell, 1(2):319–325.
108.
YooJK, BakerDP, FishEN. 2010. Interferon-beta modulates type 1 immunity during influenza virus infection. Antiviral Res, 88(1):64–71.
109.
YuanW, KrugRM. 2001. Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein. EMBO J, 20(3):362–371.
110.
YuenKY, ChanPK, PeirisM, TsangDN, QueTL, ShortridgeKF, CheungPT, ToWK, HoET, SungR, ChengAF. 1998. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet, 351(9101):467–471.
111.
ZhaoC, HsiangTY, KuoRL, KrugRM. 2010. ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells. Proc Natl Acad Sci U S A, 107(5):2253–2258.
112.
ZhouA, HasselBA, SilvermanRH. 1993. Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action. Cell, 72(5):753–765.
