Abstract
The recent research findings on influenza A virus (IAV) genome biology prompted us to present a comprehensive overview of IAV genes, protein functions, and replication cycle. The eight gene segments of the IAV genome encode 17 proteins, each having unique functions contributing to virus fitness in the host. The polymerase genes are essential determinants of IAV pathogenicity and virulence; however, other viral components also play crucial roles in the IAV replication, transmission, and adaptation. Specific adaptive mutations within polymerase (PB2, PB1, and PA) and glycoprotein—hemagglutinin (HA) and neuraminidase (NA) genes, may facilitate interspecies transmission and adaptation of IAV. The HA-NA interplay is essential for establishing the IAV infection; the low pH triggers the inactivation of HA-receptor binding, leading to significantly lower NA activities, indicating that the enzymatic function of NA is dependent on HA binding. While the HA and NA glycoproteins are required to initiate infection, M1, M2, NS1, and NEP proteins are essential for cytoplasmic trafficking of viral ribonucleoproteins (vRNPs) and the assembly of the IAV virions. The mechanisms that enable IAV to exploit the host cell resources to advance the infection are discussed. A comprehensive understanding of IAV genome biology is essential for developing antivirals to combat the IAV disease burden.
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References
Alvarado-Facundo E, Gao Y, Ribas-Aparicio RM, Jiménez-Alberto A, Weiss CD, Wang W (2015) Influenza virus M2 protein ion channel activity helps to maintain pandemic 2009 H1N1 virus hemagglutinin fusion competence during transport to the cell surface. J Virol 89:1975–1985
Amorim MJ, Bruce EA, Read EK, Foeglein A, Mahen R, Stuart AD, Digard P (2011) A Rab11- and microtubule-dependent mechanism for cytoplasmic transport of influenza A virus viral RNA. J Virol 85:4143–4156
Avilov SV, Moisy D, Naffakh N, Cusack S (2012) Influenza A virus progeny vRNP trafficking in live infected cells studied with the virus-encoded fluorescently tagged PB2 protein. Vaccine 30:7411–7417
Banerjee I, Yamauchi Y, Helenius A, Horvath P (2013) High-content analysis of sequential events during the early phase of influenza A virus infection. PLoS One 8:e68450
Bateman AC, Busch MG, Karasin AI, Bovin N, Olsen CW (2008) Amino acid 226 in the hemagglutinin of H4N6 influenza virus determines binding affinity for alpha2,6-linked sialic acid and infectivity levels in primary swine and human respiratory epithelial cells. J Virol 82:8204–8209
Baumann J, Kouassi NM, Foni E, Klenk HD, Matrosovich M (2016) H1N1 swine influenza viruses differ from avian precursors by a higher pH optimum of membrane fusion. J Virol 90:1569–1577
Belshe RB (2005) The origins of pandemic influenza–lessons from the 1918 virus. N Engl J Med 353:2209–2211
Bertram S, Glowacka I, Steffen I, Kühl A, Pöhlmann S (2010) Novel insights into proteolytic cleavage of influenza virus hemagglutinin. Rev Med Virol 20:298–310
Bertram S, Heurich A, Lavender H, Gierer S, Danisch S, Perin P, Lucas JM, Nelson PS, Pöhlmann S, Soilleux EJ (2012) Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts. PLoS One 7:e35876
Boivin S, Cusack S, Ruigrok RW, Hart DJ (2010) Influenza A virus polymerase: structural insights into replication and host adaptation mechanisms. J Biol Chem 285:28411–28417
Bolte H, Rosu ME, Hagelauer E, García-Sastre A, Schwemmle M (2019) Packaging of the influenza virus genome is governed by a plastic network of RNA- and nucleoprotein-mediated interactions. J Virol 93:e01861-e1918
Böttcher-Friebertshäuser E, Freuer C, Sielaff F, Schmidt S, Eickmann M, Uhlendorff J, Steinmetzer T, Klenk HD, Garten W (2010) Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors. J Virol 84:5605–5614
Böttcher-Friebertshäuser E, Klenk H-D, Garten W (2013) Activation of influenza viruses by proteases from host cells and bacteria in the human airway epithelium. Pathogens Dis 69:87–100
Böttcher-Friebertshäuser E, Garten W, Matrosovich M, Klenk HD (2014) The hemagglutinin: a determinant of pathogenicity. Curr Top Microbiol Immunol 385:3–34
Bouvier NM, Palese P (2008) The biology of influenza viruses. Vaccine 26:D49-53
Brunotte L, Flies J, Bolte H, Reuther P, Vreede F, Schwemmle M (2014) The nuclear export protein of H5N1 influenza A viruses recruits Matrix 1 (M1) protein to the viral ribonucleoprotein to mediate nuclear export. J Biol Chem 289:20067–20077
Bui M, Wills EG, Helenius A, Whittaker GR (2000) Role of the influenza virus M1 protein in nuclear export of viral ribonucleoproteins. J Virol 74:1781–1786
Bullido R, Gómez-Puertas P, Albo C, Portela A (2000) Several protein regions contribute to determine the nuclear and cytoplasmic localization of the influenza A virus nucleoprotein. J Gen Virol 81:135–142
Byrd-Leotis L, Cummings RD, Steinhauer DA (2017) The interplay between the host receptor and influenza virus hemagglutinin and neuraminidase. Int J Mol Sci 18:1541
Cady SD, Luo W, Hu F, Hong M (2009) Structure and function of the influenza A M2 proton channel. Biochemistry 48:7356–7364
Calder LJ, Wasilewski S, Berriman JA, Rosenthal PB (2010) Structural organization of a filamentous influenza A virus. Proc Natl Acad Sci USA 107:10685–10690
Calder LJ, Rosenthal PB (2016) Cryomicroscopy provides structural snapshots of influenza virus membrane fusion. Nat Struct Mol Biol 23:853–858
Carr SM, Carnero E, García-Sastre A, Brownlee GG, Fodor E (2006) Characterization of a mitochondrial-targeting signal in the PB2 protein of influenza viruses. Virology 344:492–508
Chakrabarti AK, Pasricha G (2013) An insight into the PB1F2 protein and its multifunctional role in enhancing the pathogenicity of the influenza A viruses. Virology 440:97–104
Chauhan RP, Gordon ML (2020) A systematic review analyzing the prevalence and circulation of influenza viruses in swine population worldwide. Pathogens 9:355
Chauhan RP, Gordon ML (2022) Review of genome sequencing technologies in molecular characterization of influenza A viruses in swine. J Vet Diagn Invest 34:177–189
Chauhan RP, Gordon ML (2021) Deciphering transmission dynamics and spillover of avian influenza viruses from avian species to swine populations globally. Virus Genes 57:541–555
Chauhan RP, Gordon ML (2022) A systematic review of influenza A virus prevalence and transmission dynamics in backyard swine populations globally. Porcine Health Manag 8:10
Chen BJ, Leser GP, Morita E, Lamb RA (2007) Influenza virus hemagglutinin and neuraminidase, but not the matrix protein, are required for assembly and budding of plasmid-derived virus-like particles. J Virol 81:7111–7123
Chen BJ, Leser GP, Jackson D, Lamb RA (2008) The influenza virus M2 protein cytoplasmic tail interacts with the M1 protein and influences virus assembly at the site of virus budding. J Virol 82:10059–10070
Chen F, Liu T, Xu J, Huang Y, Liu S, Yang J (2019) Key amino acid residues of neuraminidase involved in influenza A virus entry. Pathog Dis 77:ftz063
Chen W, Calvo PA, Malide D, Gibbs J, Schubert U, Bacik I, Basta S, O’Neill R, Schickli J, Palese P, Henklein P, Bennink JR, Yewdell JW (2001) A novel influenza A virus mitochondrial protein that induces cell death. Nat Med 7:1306–1312
Cho JH, Zhao B, Shi J, Savage N, Shen Q, Byrnes J, Yang L, Hwang W, Li P (2020) Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses. Proc Natl Acad Sci USA 117:6550–6558
Ciminski K, Pfaff F, Beer M, Schwemmle M (2020) Bats reveal the true power of influenza A virus adaptability. PLOS Pathogens 16:e1008384
Cohen M, Zhang XQ, Senaati HP, Chen HW, Varki NM, Schooley RT, Gagneux P (2013) Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase. Virol J 10:321
Coloma R, Arranz R, de la Rosa-Trevín JM, Sorzano COS, Munier S, Carlero D, Naffakh N, Ortín J, Martín-Benito J (2020) Structural insights into influenza A virus ribonucleoproteins reveal a processive helical track as transcription mechanism. Nat Microbiol 5:727–734
Costa T, Chaves AJ, Valle R, Darji A, van Riel D, Kuiken T, Majó N, Ramis A (2012) Distribution patterns of influenza virus receptors and viral attachment patterns in the respiratory and intestinal tracts of seven avian species. Vet Res 43:28
Dadonaite B, Vijayakrishnan S, Fodor E, Bhella D, Hutchinson EC (2016) Filamentous influenza viruses. J Gen Virol 97:1755–1764
Davis AM, Ramirez J, Newcomb LL (2017) Identification of influenza A nucleoprotein body domain residues essential for viral RNA expression expose antiviral target. Virology Journal 14:22–22
de Graaf M, Fouchier RA (2014) Role of receptor binding specificity in influenza A virus transmission and pathogenesis. EMBO J 33:823–841
de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau NV, Khanh TH, Dong VC, Qui PT, Cam BV, Ha do Q, Guan Y, Peiris JS, Chinh NT, Hien TT, Farrar J, (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 12:1203–1207
de Vries E, Tscherne DM, Wienholts MJ, Cobos-Jiménez V, Scholte F, García-Sastre A, Rottier PJ, de Haan CA (2011) Dissection of the influenza A virus endocytic routes reveals macropinocytosis as an alternative entry pathway. PLoS Pathog 7:e1001329
Dias A, Bouvier D, Crépin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW (2009) The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 458:914–918
Dou D, Hernández-Neuta I, Wang H, Östbye H, Qian X, Thiele S, Resa-Infante P, Kouassi NM, Sender V, Hentrich K, Mellroth P, Henriques-Normark B, Gabriel G, Nilsson M, Daniels R (2017) Analysis of IAV replication and co-infection dynamics by a versatile RNA viral genome labeling method. Cell Rep 20:251–263
Dou D, Revol R, Östbye H, Wang H, Daniels R (2018) Influenza A virus cell entry, replication, virion assembly and movement. Front Immunol 9:1581
Eisfeld AJ, Neumann G, Kawaoka Y (2015) At the centre: influenza A virus ribonucleoproteins. Nat Rev Microbiol 13:28–41
Elton D, Simpson-Holley M, Archer K, Medcalf L, Hallam R, McCauley J, Digard P (2001) Interaction of the influenza virus nucleoprotein with the cellular CRM1-mediated nuclear export pathway. J Virol 75:408–419
Gabriel G, Herwig A, Klenk HD (2008) Interaction of polymerase subunit PB2 and NP with importin alpha1 is a determinant of host range of influenza A virus. PLoS Pathog 4:e11
Gamblin SJ, Haire LF, Russell RJ, Stevens DJ, Xiao B, Ha Y, Vasisht N, Steinhauer DA, Daniels RS, Elliot A, Wiley DC, Skehel JJ (2004) The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303:1838–1842
Garten RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A, Sessions WM, Xu X, Skepner E, Deyde V, Okomo-Adhiambo M, Gubareva L, Barnes J, Smith CB, Emery SL, Hillman MJ, Rivailler P, Smagala J, de Graaf M, Burke DF, Fouchier RA, Pappas C, Alpuche-Aranda CM, López-Gatell H, Olivera H, López I, Myers CA, Faix D, Blair PJ, Yu C, Keene KM, Dotson PD Jr, Boxrud D, Sambol AR, Abid SH, St George K, Bannerman T, Moore AL, Stringer DJ, Blevins P, Demmler-Harrison GJ, Ginsberg M, Kriner P, Waterman S, Smole S, Guevara HF, Belongia EA, Clark PA, Beatrice ST, Donis R, Katz J, Finelli L, Bridges CB, Shaw M, Jernigan DB, Uyeki TM, Smith DJ, Klimov AI, Cox NJ (2009) Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 325:197–201
Garten W, Klenk HD (2008) Avian influenza: Cleavage activation of the influenza virus hemagglutinin and its role in pathogenesis. Basel, Karger 27:156–167
Guilligay D, Tarendeau F, Resa-Infante P, Coloma R, Crepin T, Sehr P, Lewis J, Ruigrok RWH, Ortin J, Hart DJ, Cusack S (2008) The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat Struct Mol Biol 15:500–506
Hale BG, Randall RE, Ortín J, Jackson D (2008) The multifunctional NS1 protein of influenza A viruses. J Gen Virol 89:2359–2376
Hara K, Schmidt FI, Crow M, Brownlee GG (2006) Amino acid residues in the N-terminal region of the PA subunit of influenza A virus RNA polymerase play a critical role in protein stability, endonuclease activity, cap binding, and virion RNA promoter binding. J Virol 80:7789–7798
Hayashi T, Wills S, Bussey KA, Takimoto T (2015) Identification of influenza A virus PB2 residues involved in enhanced polymerase activity and virus growth in mammalian cells at low temperatures. J Virol 89:8042–8049
Höfer CT, Jolmes F, Haralampiev I, Veit M, Herrmann A (2017) Influenza A virus nucleoprotein targets subnuclear structures. Cell Microbiol 19(4):e12679
Hoffmann M, Pöhlmann S (2018) Cell entry of influenza A viruses: sweet talk between HA and Ca(V)1.2. Cell Host Microbe 23:697–699
Hu Y, Sneyd H, Dekant R, Wang J (2017) Influenza A virus nucleoprotein: a highly conserved multi-functional viral protein as a hot antiviral drug target. Curr Top Med Chem 17:2271–2285
Jagger BW, Wise HM, Kash JC, Walters KA, Wills NM, Xiao YL, Dunfee RL, Schwartzman LM, Ozinsky A, Bell GL, Dalton RM, Lo A, Efstathiou S, Atkins JF, Firth AE, Taubenberger JK, Digard P (2012) An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 337:199–204
Jang J, Bae SE (2018) Comparative co-evolution analysis between the HA and NA genes of influenza A virus. Virology (Auckl) 9:1178122x18788328
Jorba N, Coloma R, Ortín J (2009) Genetic trans-complementation establishes a new model for influenza virus RNA transcription and replication. PLoS Pathog 5:e1000462
Kash JC, Tumpey TM, Proll SC, Carter V, Perwitasari O, Thomas MJ, Basler CF, Palese P, Taubenberger JK, García-Sastre A, Swayne DE, Katze MG (2006) Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443:578–581
Kawaguchi A, Matsumoto K, Nagata K (2012) YB-1 functions as a porter to lead influenza virus ribonucleoprotein complexes to microtubules. J Virol 86:11086–11095
Kawaoka Y, Krauss S, Webster RG (1989) Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics. J Virol 63:4603–4608
Kim HJ, Jeong MS, Jang SB (2021) Structure and activities of the NS1 influenza protein and progress in the development of small-molecule drugs. Int J Mol Sci 22:4242
Kordyukova LV, Shtykova EV, Baratova LA, Svergun DI, Batishchev OV (2019) Matrix proteins of enveloped viruses: a case study of influenza A virus M1 protein. J Biomol Struct Dyn 37:671–690
Krumbholz A, Philipps A, Oehring H, Schwarzer K, Eitner A, Wutzler P, Zell R (2011) Current knowledge on PB1-F2 of influenza A viruses. Med Microbiol Immunol 200:69–75
Kukol A, Hughes DJ (2014) Large-scale analysis of influenza A virus nucleoprotein sequence conservation reveals potential drug-target sites. Virology 454–455:40–47
Lai JC, Chan WW, Kien F, Nicholls JM, Peiris JS, Garcia JM (2010) Formation of virus-like particles from human cell lines exclusively expressing influenza neuraminidase. J Gen Virol 91:2322–2330
Lai JCC, Karunarathna H, Wong HH, Peiris JSM, Nicholls JM (2019) Neuraminidase activity and specificity of influenza A virus are influenced by haemagglutinin-receptor binding. Emerg Microbes Infect 8:327–338
Lampejo T (2020) Influenza and antiviral resistance: an overview. Eur J Clin Microbiol Infect Dis 39:1201–1208
Lin RW, Chen GW, Sung HH, Lin RJ, Yen LC, Tseng YL, Chang YK, Lien SP, Shih SR, Liao CL (2019) Naturally occurring mutations in PB1 affect influenza A virus replication fidelity, virulence, and adaptability. J Biomed Sci 26:55
Lin YP, Gregory V, Collins P, Kloess J, Wharton S, Cattle N, Lackenby A, Daniels R, Hay A (2010) Neuraminidase receptor binding variants of human influenza A(H3N2) viruses resulting from substitution of aspartic acid 151 in the catalytic site: a role in virus attachment? J Virol 84:6769–6781
Liu J, Li Z, Cui Y, Yang H, Shan H, Zhang C (2020) Emergence of an Eurasian avian-like swine influenza A (H1N1) virus from mink in China. Vet Microbiol 240:108509
Liu X, Yang C, Sun X, Lin X, Zhao L, Chen H, Jin M (2019) Evidence for a novel mechanism of influenza A virus host adaptation modulated by PB2-627. FEBS J 286:3389–3400
Long JC, Fodor E (2016) The PB2 Subunit of the influenza A Virus RNA polymerase is imported into the mitochondrial matrix. J Virol 90:8729–8738
Long JS, Giotis ES, Moncorgé O, Frise R, Mistry B, James J, Morisson M, Iqbal M, Vignal A, Skinner MA, Barclay WS (2016) Species difference in ANP32A underlies influenza A virus polymerase host restriction. Nature 529:101–104
MacDonald LA, Aggarwal S, Bussey KA, Desmet EA, Kim B, Takimoto T (2012) Molecular interactions and trafficking of influenza A virus polymerase proteins analyzed by specific monoclonal antibodies. Virology 426:51–59
Mancera Gracia JC, Van den Hoecke S, Saelens X, Van Reeth K (2017) Effect of serial pig passages on the adaptation of an avian H9N2 influenza virus to swine. PLoS One 12:e0175267
Mänz B, Schwemmle M, Brunotte L (2013) Adaptation of avian influenza A virus polymerase in mammals to overcome the host species barrier. J Virol 87:7200–7209
Mazur I, Anhlan D, Mitzner D, Wixler L, Schubert U, Ludwig S (2008) The proapoptotic influenza A virus protein PB1-F2 regulates viral polymerase activity by interaction with the PB1 protein. Cell Microbiol 10:1140–1152
McAuley JL, Chipuk JE, Boyd KL, Van De Velde N, Green DR, McCullers JA (2010) PB1-F2 proteins from H5N1 and 20 century pandemic influenza viruses cause immunopathology. PLoS Pathog 6:e1001014
McAuley JL, Corcilius L, Tan HX, Payne RJ, McGuckin MA, Brown LE (2017) The cell surface mucin MUC1 limits the severity of influenza A virus infection. Mucosal Immunol 10:1581–1593
McAuley JL, Gilbertson BP, Trifkovic S, Brown LE, McKimm-Breschkin JL (2019) Influenza virus neuraminidase structure and functions. Front Microbiol 10:39
McGeoch D, Fellner P, Newton C (1976) Influenza virus genome consists of eight distinct RNA species. Proc Natl Acad Sci U S A 73:3045–3049
McKimm-Breschkin JL, Williams J, Barrett S, Jachno K, McDonald M, Mohr PG, Saito T, Tashiro M (2013) Reduced susceptibility to all neuraminidase inhibitors of influenza H1N1 viruses with haemagglutinin mutations and mutations in non-conserved residues of the neuraminidase. J Antimicrob Chemother 68:2210–2221
Mehle A, Dugan VG, Taubenberger JK, Doudna JA (2012) Reassortment and mutation of the avian influenza virus polymerase PA subunit overcome species barriers. J Virol 86:1750–1757
Mena I, Nelson MI, Quezada-Monroy F, Dutta J, Cortes-Fernández R, Lara-Puente JH, Castro-Peralta F, Cunha LF, Trovão NS, Lozano-Dubernard B, Rambaut A, van Bakel H, García-Sastre A (2016) Origins of the 2009 H1N1 influenza pandemic in swine in Mexico. Elife 5:e16777
Moeller A, Kirchdoerfer RN, Potter CS, Carragher B, Wilson IA (2012) Organization of the influenza virus replication machinery. Science 338:1631–1634
Mohr PG, Deng YM, McKimm-Breschkin JL (2015) The neuraminidases of MDCK grown human influenza A(H3N2) viruses isolated since 1994 can demonstrate receptor binding. Virol J 12:67
Momose F, Sekimoto T, Ohkura T, Jo S, Kawaguchi A, Nagata K, Morikawa Y (2011) Apical transport of influenza A virus ribonucleoprotein requires Rab11-positive recycling endosome. PLoS One 6:e21123
Muramoto Y, Noda T, Kawakami E, Akkina R, Kawaoka Y (2013) Identification of novel influenza A virus proteins translated from PA mRNA. J Virol 87:2455–2462
Nelli RK, Kuchipudi SV, White GA, Perez BB, Dunham SP, Chang K-C (2010) Comparative distribution of human and avian type sialic acid influenza receptors in the pig. BMC Vet Res 6:4
Neumann G, Hughes MT, Kawaoka Y (2000) Influenza A virus NS2 protein mediates vRNP nuclear export through NES-independent interaction with hCRM1. EMBO J 19:6751–6758
Neumann G, Noda T, Kawaoka Y (2009) Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459:931–939
Newby CM, Sabin L, Pekosz A (2007) The RNA binding domain of influenza A virus NS1 protein affects secretion of tumor necrosis factor alpha, interleukin-6, and interferon in primary murine tracheal epithelial cells. J Virol 81:9469–9480
Newcomb LL, Kuo RL, Ye Q, Jiang Y, Tao YJ, Krug RM (2009) Interaction of the influenza A virus nucleocapsid protein with the viral RNA polymerase potentiates unprimed viral RNA replication. J Virol 83:29–36
Nicholls JM, Bourne AJ, Chen H, Guan Y, Peiris JSM (2007) Sialic acid receptor detection in the human respiratory tract: evidence for widespread distribution of potential binding sites for human and avian influenza viruses. Respir Res 8:73
O’Neill RE, Talon J, Palese P (1998) The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. EMBO J 17:288–296
Obayashi E, Yoshida H, Kawai F, Shibayama N, Kawaguchi A, Nagata K, Tame JR, Park SY (2008) The structural basis for an essential subunit interaction in influenza virus RNA polymerase. Nature 454:1127–1131
Ozawa M, Fujii K, Muramoto Y, Yamada S, Yamayoshi S, Takada A, Goto H, Horimoto T, Kawaoka Y (2007) Contributions of two nuclear localization signals of influenza A virus nucleoprotein to viral replication. J Virol 81:30–41
Palese P, Tobita K, Ueda M, Compans RW (1974) Characterization of temperature sensitive influenza virus mutants defective in neuraminidase. Virology 61:397–410
Parrish CR, Kawaoka Y (2005) The origins of new pandemic viruses: the acquisition of new host ranges by canine parvovirus and influenza A viruses. Annu Rev Microbiol 59:553–586
Paterson D, Fodor E (2012) Emerging roles for the influenza A virus nuclear export protein (NEP). PLoS Pathog 8:e1003019
Peitsch C, Klenk HD, Garten W, Böttcher-Friebertshäuser E (2014) Activation of influenza A viruses by host proteases from swine airway epithelium. J Virol 88:282–291
Pereira CF, Read EKC, Wise HM, Amorim MJ, Digard P (2017) Influenza A virus NS1 protein promotes efficient nuclear export of unspliced viral M1 mRNA. J Virol 91:e00528-e617
Peukes J, Xiong X, Erlendsson S, Qu K, Wan W, Calder LJ, Schraidt O, Kummer S, Freund SMV, Kräusslich HG, Briggs JAG (2020) The native structure of the assembled matrix protein 1 of influenza A virus. Nature 587:495–498
Plotch SJ, Bouloy M, Ulmanen I, Krug RM (1981) A unique cap(m7G pppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell 23:847–858
Rachakonda PS, Veit M, Korte T, Ludwig K, Böttcher C, Huang Q, Schmidt MF, Herrmann A (2007) The relevance of salt bridges for the stability of the influenza virus hemagglutinin. FASEB J 21:995–1002
Reid AH, Fanning TG, Janczewski TA, Taubenberger JK (2000) Characterization of the 1918 “Spanish” influenza virus neuraminidase gene. Proc Natl Acad Sci U S A 97:6785–6790
Reuther P, Giese S, Götz V, Kilb N, Mänz B, Brunotte L, Schwemmle M (2014) Adaptive mutations in the nuclear export protein of human-derived H5N1 strains facilitate a polymerase activity-enhancing conformation. J Virol 88:263–271
Rialdi A, Hultquist J, Jimenez-Morales D, Peralta Z, Campisi L, Fenouil R, Moshkina N, Wang ZZ, Laffleur B, Kaake RM, McGregor MJ, Haas K, Pefanis E, Albrecht RA, Pache L, Chanda S, Jen J, Ochando J, Byun M, Basu U, García-Sastre A, Krogan N, van Bakel H, Marazzi I (2017) The RNA exosome syncs IAV-RNAPII transcription to promote viral ribogenesis and infectivity. Cell 169:679-692.e614
Robb NC, Smith M, Vreede FT, Fodor E (2009) NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome. J Gen Virol 90:1398–1407
Robb NC, Chase G, Bier K, Vreede FT, Shaw PC, Naffakh N, Schwemmle M, Fodor E (2011) The influenza A virus NS1 protein interacts with the nucleoprotein of viral ribonucleoprotein complexes. J Virol 85:5228–5231
Rosário-Ferreira N, Preto AJ, Melo R, Moreira IS, Brito RMM (2020) The central role of non-structural protein 1 (NS1) in influenza biology and infection. Int J Mol Sci 21:1511
Rossman JS, Jing X, Leser GP, Lamb RA (2010) Influenza virus M2 protein mediates ESCRT-independent membrane scission. Cell 142:902–913
Russier M, Yang G, Rehg JE, Wong SS, Mostafa HH, Fabrizio TP, Barman S, Krauss S, Webster RG, Webby RJ, Russell CJ (2016) Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein. Proc Natl Acad Sci U S A 113:1636–1641
Rust MJ, Lakadamyali M, Zhang F, Zhuang X (2004) Assembly of endocytic machinery around individual influenza viruses during viral entry. Nat Struct Mol Biol 11:567–573
Sakai T, Nishimura SI, Naito T, Saito M (2017) Influenza A virus hemagglutinin and neuraminidase act as novel motile machinery. Sci Rep 7:45043
Scholtissek C, Rohde W, Von Hoyningen V, Rott R (1978) On the origin of the human influenza virus subtypes H2N2 and H3N2. Virology 87:13–20
Selman M, Dankar SK, Forbes NE, Jia JJ, Brown EG (2012) Adaptive mutation in influenza A virus non-structural gene is linked to host switching and induces a novel protein by alternative splicing. Emerg Microbes Infect 1:e42
Şenbaş Akyazi B, Pirinçal A, Kawaguchi A, Nagata K, Turan K (2020) Interaction of influenza A virus NS2/NEP protein with the amino-terminal part of Nup214. Turk J Biol 44:82–92
Shen YF, Chen YH, Chu SY, Lin MI, Hsu HT, Wu PY, Wu CJ, Liu HW, Lin FY, Lin G, Hsu PH, Yang AS, Cheng YS, Wu YT, Wong CH, Tsai MD (2011) E339...R416 salt bridge of nucleoprotein as a feasible target for influenza virus inhibitors. Proc Natl Acad Sci USA 108:16515–16520
Shimizu T, Takizawa N, Watanabe K, Nagata K, Kobayashi N (2011) Crucial role of the influenza virus NS2 (NEP) C-terminal domain in M1 binding and nuclear export of vRNP. FEBS Lett 585:41–46
Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y (2006) Influenza virus receptors in the human airway. Nature 440:435–436
Shirley M (2020) Baloxavir Marboxil: A review in acute uncomplicated influenza. Drugs 80:1109–1118
Shtykova EV, Dadinova LA, Fedorova NV, Golanikov AE, Bogacheva EN, Ksenofontov AL, Baratova LA, Shilova LA, Tashkin VY, Galimzyanov TR, Jeffries CM, Svergun DI, Batishchev OV (2017) Influenza virus matrix protein M1 preserves its conformation with pH, changing multimerization state at the priming stage due to electrostatics. Sci Rep 7:16793
Smith GJD, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S, Peiris JSM, Guan Y, Rambaut A (2009) Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 459:1122–1125
Steel J, Lowen AC, Mubareka S, Palese P (2009) Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog 5:e1000252
Stevens J, Blixt O, Tumpey TM, Taubenberger JK, Paulson JC, Wilson IA (2006) Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312:404–410
Stewart M (2007) Molecular mechanism of the nuclear protein import cycle. Nat Rev Mol Cell Biol 8:195–208
Szeto WC, Hsia HP, Tang YS, Shaw PC (2020) Interaction between influenza A virus nucleoprotein and PB2 cap-binding domain is mediated by RNA. PLoS One 15:e0239899
Takahashi T, Suzuki T (2015) Low-pH stability of influenza A virus sialidase contributing to virus replication and pandemic. Biol Pharm Bull 38:817–826
Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG (2005) Characterization of the 1918 influenza virus polymerase genes. Nature 437:889–893
Tauber S, Ligertwood Y, Quigg-Nicol M, Dutia BM, Elliott RM (2012) Behaviour of influenza A viruses differentially expressing segment 2 gene products in vitro and in vivo. J Gen Virol 93:840–849
te Velthuis AJW, Fodor E (2016) Influenza virus RNA polymerase: insights into the mechanisms of viral RNA synthesis. Nat Rev Microbiol 14:479–493
Thaa B, Herrmann A, Veit M (2009) The polybasic region is not essential for membrane binding of the matrix protein M1 of influenza virus. Virology 383:150–155
Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, Yang H, Chen X, Recuenco S, Gomez J, Chen LM, Johnson A, Tao Y, Dreyfus C, Yu W, McBride R, Carney PJ, Gilbert AT, Chang J, Guo Z, Davis CT, Paulson JC, Stevens J, Rupprecht CE, Holmes EC, Wilson IA, Donis RO (2013) New world bats harbor diverse influenza A viruses. PLoS Pathog 9:e1003657
Trebbien R, Larsen LE, Viuff BM (2011) Distribution of sialic acid receptors and influenza A virus of avian and swine origin in experimentally infected pigs. Virol J 8:434
Tsai CF, Lin HY, Hsu WL, Tsai CH (2017) The novel mitochondria localization of influenza A virus NS1 visualized by FlAsH labeling. FEBS Open Bio 7:1960–1971
Vajda J, Weber D, Brekel D, Hundt B, Müller E (2016) Size distribution analysis of influenza virus particles using size exclusion chromatography. J Chromatogr A 1465:117–125
Vasin AV, Temkina OA, Egorov VV, Klotchenko SA, Plotnikova MA, Kiselev OI (2014) Molecular mechanisms enhancing the proteome of influenza A viruses: an overview of recently discovered proteins. Virus Res 185:53–63
Venter M, Treurnicht FK, Buys A, Tempia S, Samudzi R, McAnerney J, Jacobs CA, Thomas J, Blumberg L (2017) Risk of human infections with highly pathogenic H5N2 and low pathogenic H7N1 avian influenza strains during outbreaks in ostriches in South Africa. J Infect Dis 216:S512-s519
Vreede FT, Jung TE, Brownlee GG (2004) Model suggesting that replication of influenza virus is regulated by stabilization of replicative intermediates. J Virol 78:9568–9572
Wang Q, Li Q, Liu T, Chang G, Sun Z, Gao Z, Wang F, Zhou H, Liu R, Zheng M, Cui H, Chen G, Li H, Yuan X, Wen J, Peng D, Zhao G (2018) Host interaction analysis of PA-N155 and PA-N182 in chicken cells reveals an essential role of UBA52 for replication of H5N1 avian influenza virus. Front Microbiol 9:936
Wendel I, Rubbenstroth D, Doedt J, Kochs G, Wilhelm J, Staeheli P, Klenk HD, Matrosovich M (2015) The avian-origin PB1 gene segment facilitated replication and transmissibility of the H3N2/1968 pandemic influenza virus. J Virol 89:4170–4179
White JM, Whittaker GR (2016) fusion of enveloped viruses in endosomes. Traffic 17:593–614
Williams GD, Townsend D, Wylie KM, Kim PJ, Amarasinghe GK, Kutluay SB, Boon ACM (2018) Nucleotide resolution mapping of influenza A virus nucleoprotein-RNA interactions reveals RNA features required for replication. Nat Commun 9:465
Wise HM, Foeglein A, Sun J, Dalton RM, Patel S, Howard W, Anderson EC, Barclay WS, Digard P (2009) A complicated message: Identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J Virol 83:8021–8031
Wise HM, Hutchinson EC, Jagger BW, Stuart AD, Kang ZH, Robb N, Schwartzman LM, Kash JC, Fodor E, Firth AE, Gog JR, Taubenberger JK, Digard P (2012) Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain. PLoS Pathog 8:e1002998
Wu CY, Lin CW, Tsai TI, Lee CD, Chuang HY, Chen JB, Tsai MH, Chen BR, Lo PW, Liu CP, Shivatare VS, Wong CH (2017) Influenza A surface glycosylation and vaccine design. Proc Natl Acad Sci U S A 114:280–285
Xu G, Zhang X, Liu Q, Bing G, Hu Z, Sun H, Xiong X, Jiang M, He Q, Wang Y, Pu J, Guo X, Yang H, Liu J, Sun Y (2017) PA-X protein contributes to virulence of triple-reassortant H1N2 influenza virus by suppressing early immune responses in swine. Virology 508:45–53
Yamada H, Chounan R, Higashi Y, Kurihara N, Kido H (2004) Mitochondrial targeting sequence of the influenza A virus PB1-F2 protein and its function in mitochondria. FEBS Lett 578:331–336
Yamada S, Hatta M, Staker BL, Watanabe S, Imai M, Shinya K, Sakai-Tagawa Y, Ito M, Ozawa M, Watanabe T, Sakabe S, Li C, Kim JH, Myler PJ, Phan I, Raymond A, Smith E, Stacy R, Nidom CA, Lank SM, Wiseman RW, Bimber BN, O’Connor DH, Neumann G, Stewart LJ, Kawaoka Y (2010) Biological and structural characterization of a host-adapting amino acid in influenza virus. PLoS Pathog 6:e1001034
Yang J, Liu S, Du L, Jiang S (2016) A new role of neuraminidase (NA) in the influenza virus life cycle: implication for developing NA inhibitors with novel mechanism of action. Rev Med Virol 26:242–250
Yang Y, Halloran ME, Sugimoto JD, Longini IM Jr (2007) Detecting human-to-human transmission of avian influenza A (H5N1). Emerg Infect Dis 13:1348–1353
Yewdell JW, Ince WL (2012) Virology. Frameshifting to PA-X influenza. Science 337:164–165
Yoshizumi T, Ichinohe T, Sasaki O, Otera H, Kawabata S, Mihara K, Koshiba T (2014) Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity. Nat Commun 5:4713
Yu M, Liu X, Cao S, Zhao Z, Zhang K, Xie Q, Chen C, Gao S, Bi Y, Sun L, Ye X, Gao GF, Liu W (2012) Identification and characterization of three novel nuclear export signals in the influenza A virus nucleoprotein. J Virol 86:4970–4980
Yuan P, Bartlam M, Lou Z, Chen S, Zhou J, He X, Lv Z, Ge R, Li X, Deng T, Fodor E, Rao Z, Liu Y (2009) Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site. Nature 458:909–913
Zhang X, Li Y, Jin S, Zhang Y, Sun L, Hu X, Zhao M, Li F, Wang T, Sun W, Feng N, Wang H, He H, Zhao Y, Yang S, Xia X, Gao Y (2021) PB1 S524G mutation of wild bird-origin H3N8 influenza A virus enhances virulence and fitness for transmission in mammals. Emerg Microbes Infect 10:1038–1051
Zhao P, Sun L, Xiong J, Wang C, Chen L, Yang P, Yu H, Yan Q, Cheng Y, Jiang L, Chen Y, Zhao G, Jiang Q, Xiong C (2019) Semiaquatic mammals might be intermediate hosts to spread avian influenza viruses from avian to human. Sci Rep 9:11641
Zhu X, McBride R, Nycholat CM, Yu W, Paulson JC, Wilson IA (2012) Influenza virus neuraminidases with reduced enzymatic activity that avidly bind sialic Acid receptors. J Virol 86:13371–13383
Zimmermann P, Mänz B, Haller O, Schwemmle M, Kochs G (2011) The viral nucleoprotein determines Mx sensitivity of influenza A viruses. J Virol 85:8133–8140
Acknowledgements
The authors acknowledge the College of Health Sciences at the University of KwaZulu-Natal, Durban, granting a three-year CHS research scholarship to Ravendra P. Chauhan. The authors are thankful to the reviewers for performing a critical review of the manuscript, which helped the authors to improve the manuscript.
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Conceptualization: RPC and MLG, Methodology: RPC, Formal analysis and investigation: RPC, Preparation of Figures and Table: RPC, Writing – original draft preparation: RPC, Writing – review and editing: RPC and MLG, Supervision: MLG. Both authors have critically read the manuscript and agreed to the publication.
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Chauhan, R.P., Gordon, M.L. An overview of influenza A virus genes, protein functions, and replication cycle highlighting important updates. Virus Genes 58, 255–269 (2022). https://doi.org/10.1007/s11262-022-01904-w
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DOI: https://doi.org/10.1007/s11262-022-01904-w