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Review Article

Too young to die? How aging affects cellular innate immune responses to influenza virus and disease severity

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Pages 1629-1646 | Received 03 Mar 2021, Accepted 26 May 2021, Published online: 21 Jun 2021

References

  • Paget J, Spreeuwenberg P, Charu V, et al. Global mortality associated with seasonal influenza epidemics: new burden estimates and predictors from the GLaMOR project. J Glob Health. 2019;9(2):020421.
  • Clohisey S, Baillie JK. Host susceptibility to severe influenza A virus infection. Crit Care. 2019;23(1):303.
  • Sellers SA, Hagan RS, Hayden FG, et al. The hidden burden of influenza: a review of the extra-pulmonary complications of influenza infection. Influenza Other Respir Viruses. 2017;11(5):372–393.
  • Short KR, Kroeze E, Fouchier RAM, et al. Pathogenesis of influenza-induced acute respiratory distress syndrome. Lancet Infect Dis. 2014;14(1):57–69.
  • van der Sluijs KF, Van Der Poll T, Lutter R, et al. Bench-to-bedside review: bacterial pneumonia with influenza - pathogenesis and clinical implications. Crit Care. 2010;14(2):219.
  • Morris DE, Cleary DW, Clarke SC, et al. Secondary bacterial infections associated with influenza pandemics. Front Microbiol. 2017;8:1041.
  • United Nations Department of Economic and Social Affairs. World population ageing 2019: highlights (ST/ESA/SER.A/430). 2019. https://www.un.org/en/development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2019-Highlights.pdf
  • Zhou H, Thompson WW, Viboud CG, et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008. Clin Infect Dis. 2012;54(10):1427–1436.
  • Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289(2):179–186.
  • Laghlali G, Lawlor KE, Tate MD, et al. Die another way: interplay between influenza A virus, inflammation and cell death. Viruses. 2020;12(4):401.
  • Newton AH, Cardani A, Braciale TJ, et al. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin Immunopathol. 2016;38(4):471–482.
  • Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol. 2014;14(5):315–328.
  • Brandenberger C, Muhlfeld C. Mechanisms of lung aging. Cell Tissue Res. 2017;367(3):469–480.
  • Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes?. Front Immunol. 2017;8:1960.
  • Zhou K, Wang J, Li A, et al. Swift and strong NK cell responses protect 129 mice against high-dose influenza virus infection. J Immunol. 2016;196(4):1842–1854.
  • Srivastava B, Blazejewska P, Hessmann M, et al. Host genetic background strongly influences the response to influenza a virus infections. PLoS One. 2009;4(3):e4857.
  • Staeheli P, Grob R, Meier E, et al. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Mol Cell Biol. 1988;8(10):4518–4523.
  • Pillai PS, Molony RD, Martinod K, et al. Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science. 2016;352(6284):463–466.
  • Tumpey TM, Szretter KJ, Van Hoeven N, et al. The Mx1 gene protects mice against the pandemic 1918 and highly lethal human H5N1 influenza viruses. J Virol. 2007;81(19):10818–10821.
  • Shin DL, Hatesuer B, Bergmann S, et al. Protection from severe influenza virus infections in mice carrying the Mx1 influenza virus resistance gene strongly depends on genetic background. J Virol. 2015;89(19):9998–10009.
  • Po JL, Gardner EM, Anaraki F, et al. Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection. Mech Ageing Dev. 2002;123(8):1167–1181.
  • Toapanta FR, Ross TM. Impaired immune responses in the lungs of aged mice following influenza infection. Respir Res. 2009;10(1):112.
  • Stout-Delgado HW, Vaughan SE, Shirali AC, et al. Impaired NLRP3 inflammasome function in elderly mice during influenza infection is rescued by treatment with nigericin. J Immunol. 2012;188(6):2815–2824.
  • Zhao J, Zhao J, Legge K, et al. Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J Clin Invest. 2011;121(12):4921–4930.
  • Wong CK, Smith CA, Sakamoto K, et al. Aging impairs alveolar macrophage phagocytosis and increases influenza-induced mortality in mice. J Immunol. 2017;199(3):1060–1068.
  • Cho SJ, Hong KS, Schenck E, et al. Decreased IDO1 dependent tryptophan metabolism in aged lung during influenza. Eur Respir J. 2020;57(5):2000443.
  • D’Souza SS, Shen X, Fung ITH, et al. Compartmentalized effects of aging on group 2 innate lymphoid cell development and function. Aging Cell. 2019;18(6):e13019.
  • Gardner EM. Caloric restriction decreases survival of aged mice in response to primary influenza infection. J Gerontol A Biol Sci Med Sci. 2005;60(6):688–694.
  • Nogusa S, Ritz BW, Kassim SH, et al. Characterization of age-related changes in natural killer cells during primary influenza infection in mice. Mech Ageing Dev. 2008;129(4):223–230.
  • Kulkarni U, Zemans RL, Smith CA, et al. Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality. Mucosal Immunol. 2019;12(2):545–554.
  • Josset L, Engelmann F, Haberthur K, et al. Increased viral loads and exacerbated innate host responses in aged macaques infected with the 2009 pandemic H1N1 influenza A virus. J Virol. 2012;86(20):11115–11127.
  • Lu J, Duan X, Zhao W, et al. Aged mice are more resistant to influenza virus infection due to reduced inflammation and lung pathology. Aging Dis. 2018;9(3):358–373.
  • Smith CA, Kulkarni U, Chen J, et al. Influenza virus inoculum volume is critical to elucidate age-dependent mortality in mice. Aging Cell. 2019;18(2):e12893.
  • Nobusawa E, Sato K. Comparison of the mutation rates of human influenza A and B viruses. J Virol. 2006;80(7):3675–3678.
  • Samji T. Influenza A: understanding the viral life cycle. Yale J Biol Med. 2009;82(4):153–159.
  • Compans RW, Klenk HD, Caliguiri LA, et al. Influenza virus proteins. I. Analysis of polypeptides of the virion and identification of spike glycoproteins. Virology. 1970;42(4):880–889.
  • Belser JA, Bridges CB, Katz JM, et al. Past, present, and possible future human infection with influenza virus A subtype H7. Emerg Infect Dis. 2009;15(6):859–865.
  • Ong JD, Mansell A, Tate MD, et al. Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection. J Leukoc Biol. 2017;101(4):863–874.
  • Odendall C, Kagan JC. The unique regulation and functions of type III interferons in antiviral immunity. Curr Opin Virol. 2015;12:47–52.
  • Schoggins JW. Interferon-stimulated genes: what do they all do?. Annu Rev Virol. 2019;6(1):567–584.
  • Molony RD, Malawista A, Montgomery RR, et al. Reduced dynamic range of antiviral innate immune responses in aging. Exp Gerontol. 2018;107:130–135.
  • Thomas BJ, Porritt RA, Hertzog PJ, et al. Glucocorticosteroids enhance replication of respiratory viruses: effect of adjuvant interferon. Sci Rep. 2014;4(1):7176.
  • Tate MD, Schilter HC, Brooks AG, et al. Responses of mouse airway epithelial cells and alveolar macrophages to virulent and avirulent strains of influenza A virus. Viral Immunol. 2011;24(2):77–88.
  • Tate MD, Pickett DL, van Rooijen N, et al. Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J Virol. 2010;84(15):7569–7580.
  • Rossman JS, Lamb RA. Influenza virus assembly and budding. Virology. 2011;411(2):229–236.
  • Seo SH, Webster RG. Tumor necrosis factor alpha exerts powerful anti-influenza virus effects in lung epithelial cells. J Virol. 2002;76(3):1071–1076.
  • Herold S, von Wulffen W, Steinmueller M, et al. Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules. J Immunol. 2006;177(3):1817–1824.
  • Jewell NA, Vaghefi N, Mertz SE, et al. Differential type I interferon induction by respiratory syncytial virus and influenza a virus in vivo. J Virol. 2007;81(18):9790–9800.
  • Matsukura S, Kokubu F, Kubo H, et al. Expression of RANTES by normal airway epithelial cells after influenza virus A infection. Am J Respir Cell Mol Biol. 1998;18(2):255–264.
  • Matsukura S, Kokubu F, Noda H, et al. Expression of IL-6, IL-8, and RANTES on human bronchial epithelial cells, NCI-H292, induced by influenza virus A. J Allergy Clin Immunol. 1996;98(6):1080–1087.
  • Choi AM, Jacoby DB. Influenza virus A infection induces interleukin-8 gene expression in human airway epithelial cells. FEBS Lett. 1992;309(3):327–329.
  • Arndt U, Wennemuth G, Barth P, et al. Release of macrophage migration inhibitory factor and CXCL8/interleukin-8 from lung epithelial cells rendered necrotic by influenza A virus infection. J Virol. 2002;76(18):9298–9306.
  • Chan MC, Cheung CY, Chui WH, et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res. 2005;6(1):135.
  • Wareing MD, Lyon AB, Lu B, et al. Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice. J Leukoc Biol. 2004;76(4):886–895.
  • Sprenger H, Meyer RG, Kaufmann A, et al. Selective induction of monocyte and not neutrophil-attracting chemokines after influenza A virus infection. J Exp Med. 1996;184(3):1191–1196.
  • Wang J, Nikrad MP, Travanty EA, et al. Innate immune response of human alveolar macrophages during influenza A infection. PLoS One. 2012;7(3):e29879.
  • Chan RW, Yuen KM, Yu WC, et al. Influenza H5N1 and H1N1 virus replication and innate immune responses in bronchial epithelial cells are influenced by the state of differentiation. PLoS One. 2010;5(1):e8713.
  • Cheung CY, Poon LL, Lau AS, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?. Lancet. 2002;360(9348):1831–1837.
  • Yuen KY, Chan PK, Peiris M, et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet. 1998;351(9101):467–471.
  • To KF, Chan PK, Chan KF, et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol. 2001;63(3):242–246.
  • de Jong MD, Hien TT. Avian influenza A (H5N1). J Clin Virol. 2006;35(1):2–13.
  • Tate MD, Ioannidis LJ, Croker B, et al. The role of neutrophils during mild and severe influenza virus infections of mice. PLoS One. 2011;6(3):e17618.
  • Bawazeer A, Rosli S, Harpur CM, et al. IL-1β exacerbates disease and is a potential therapeutic target to reduce pulmonary inflammation during severe influenza A virus infection. Immunol Cell Biol. 2021. DOI:10.1111/imcb.12459.
  • Monticelli LA, Sonnenberg GF, Abt MC, et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011;12(11):1045–1054.
  • Califano D, Furuya Y, Roberts S, et al. IFN-γ increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells. Mucosal Immunol. 2018;11(1):209–219.
  • Li BWS, Mjw DB, Lukkes M, et al. T cells and ILC2s are major effector cells in influenza-induced exacerbation of allergic airway inflammation in mice. Eur J Immunol. 2019;49(1):144–156.
  • Muizer K, De Vries M, Timens W, et al. The effect of age on lung epithelial barrier function. Eur Respir J. 2018(52):OA2124.
  • Zheng D, Limmon GV, Yin L, et al. A cellular pathway involved in clara cell to alveolar type II cell differentiation after severe lung injury. PLoS One. 2013;8(8):e71028.
  • Yin L, Zheng D, Limmon GV, et al. Aging exacerbates damage and delays repair of alveolar epithelia following influenza viral pneumonia. Respir Res. 2014;15(1):116.
  • Watson JK, Sanders P, Dunmore R, et al. Distal lung epithelial progenitor cell function declines with age. Sci Rep. 2020;10(1):10490.
  • Fels AO, Cohn ZA. The alveolar macrophage. J Appl Physiol (1985). 1986;60(2):353–369.
  • Holt PG. Inhibitory activity of unstimulated alveolar macrophages on T-Lymphocyte blastogenic response 1. Am Rev Respir Dis. 1978;118(4):791–793.
  • Hashimoto D, Chow A, Noizat C, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38(4):792–804.
  • Tarling JD, Lin HS, Hsu S, et al. Self-renewal of pulmonary alveolar macrophages: evidence from radiation chimera studies. J Leukoc Biol. 1987;42(5):443–446.
  • Hartnell A, Steel J, Turley H, et al. Characterization of human sialoadhesin, a sialic acid binding receptor expressed by resident and inflammatory macrophage populations. Blood. 2001;97(1):288–296.
  • Ducreux J, Crocker PR, Vanbever R, et al. Analysis of sialoadhesin expression on mouse alveolar macrophages. Immunol Lett. 2009;124:77–80.
  • Bedoret D, Wallemacq H, Marichal T, et al. Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice. J Clin Invest. 2009;119(12):3723–3738.
  • Hoffmann FM, Berger JL, Lingel I, et al. Distribution and interaction of murine pulmonary phagocytes in the naive and allergic lung. Front Immunol. 2018;9:1046.
  • Lagranderie M, Nahori MA, Balazuc AM, et al. Dendritic cells recruited to the lung shortly after intranasal delivery of mycobacterium bovis BCG drive the primary immune response towards a type 1 cytokine production. Immunology. 2003;108(3):352–364.
  • Franke-Ullmann G, Pfortner C, Walter P, et al. Characterization of murine lung interstitial macrophages in comparison with alveolar macrophages in vitro. J Immunol. 1996;157(7):3097–3104.
  • Londrigan SL, Tate MD, Brooks AG, et al. Cell-surface receptors on macrophages and dendritic cells for attachment and entry of influenza virus. J Leukoc Biol. 2012;92(1):97–106.
  • Tate MD, Brooks AG, Reading PC, et al. Inhibition of lectin-mediated innate host defences in vivo modulates disease severity during influenza virus infection. Immunol Cell Biol. 2011;89(3):482–491.
  • Tate MD, Brooks AG, Reading PC, et al. Specific sites of N-linked glycosylation on the hemagglutinin of H1N1 subtype influenza A virus determine sensitivity to inhibitors of the innate immune system and virulence in mice. J Immunol. 2011;187(4):1884–1894.
  • Meischel T, Villalon-Letelier F, Saunders PM, et al. Influenza A virus interactions with macrophages: lessons from epithelial cells. Cell Microbiol. 2020;22(5):e13170.
  • Short KR, Brooks AG, Reading PC, et al. The fate of influenza A virus after infection of human macrophages and dendritic cells. J Gen Virol. 2012;93(11):2315–2325.
  • Gorski SA, Hahn YS, Braciale TJ, et al. Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. PLoS Pathog. 2013;9(9):e1003615.
  • Chang YJ, Kim HY, Albacker LA, et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol. 2011;12(7):631–638.
  • McGill J, Van Rooijen N, Legge KL, et al. Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs. J Exp Med. 2008;205(7):1635–1646.
  • Tumpey TM, Garcia-Sastre A, Taubenberger JK, et al. Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J Virol. 2005;79(23):14933–14944.
  • Wijburg OL, DiNatale S, Vadolas J, et al. Alveolar macrophages regulate the induction of primary cytotoxic T-lymphocyte responses during influenza virus infection. J Virol. 1997;71(12):9450–9457.
  • Murphy EA, Davis JM, McClellan JL, et al. Susceptibility to infection and inflammatory response following influenza virus (H1N1, A/PR/8/34) challenge: role of macrophages. J Interferon Cytokine Res. 2011;31(6):501–508.
  • Narasaraju T, Yang E, Samy RP, et al. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol. 2011;179(1):199–210.
  • Purnama C, Ng SL, Tetlak P, et al. Transient ablation of alveolar macrophages leads to massive pathology of influenza infection without affecting cellular adaptive immunity. Eur J Immunol. 2014;44(7):2003–2012.
  • Seo SU, Kwon HJ, Ko HJ, et al. Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice. PLoS Pathog. 2011;7(2):e1001304.
  • Brandes M, Klauschen F, Kuchen S, et al. A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection. Cell. 2013;154(1):197–212.
  • Rosli S, Kirby FJ, Lawlor KE, et al. Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection. Br J Pharmacol. 2019;176(19):3834–3844.
  • Koerner I, Kochs G, Kalinke U, et al. Protective role of beta interferon in host defense against influenza A virus. J Virol. 2007;81(4):2025–2030.
  • Dessing MC, van der Sluijs KF, Florquin S, et al. Monocyte chemoattractant protein 1 contributes to an adequate immune response in influenza pneumonia. Clin Immunol. 2007;125(3):328–336.
  • Dawson TC, Beck MA, Kuziel WA, et al. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am J Pathol. 2000;156(6):1951–1959.
  • Lai C, Wang K, Zhao Z, et al. C-C motif chemokine ligand 2 (CCL2) mediates acute lung injury induced by lethal influenza H7N9 virus. Front Microbiol. 2017;8:587.
  • Herold S, Steinmueller M, von Wulffen W, et al. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J Exp Med. 2008;205(13):3065–3077.
  • Lin KL, Suzuki Y, Nakano H, et al. CCR2 +Monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J Immunol. 2008;180(4):2562–2572.
  • Hernandez-Vargas EA, Wilk E, Canini L, et al. Effects of aging on influenza virus infection dynamics. J Virol. 2014;88(8):4123–4131.
  • Higashimoto Y, Fukuchi Y, Shimada Y, et al. The effects of aging on the function of alveolar macrophages in mice. Mech Ageing Dev. 1993;69(3):207–217.
  • Ghoneim HE, Thomas PG, McCullers JA, et al. Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections. J Immunol. 2013;191(3):1250–1259.
  • Califano D, Furuya Y, Metzger DW, et al. Effects of influenza on alveolar macrophage viability are dependent on mouse genetic strain. J Immunol. 2018;201(1):134–144.
  • Roquilly A, Jacqueline C, Davieau M, et al. Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis. Nat Immunol. 2020;21(6):636–648.
  • Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–252.
  • Sung SS, Fu SM, Rose CE Jr., et al. A major lung CD103 (αE)-β7 integrin-positive epithelial dendritic cell population expressing langerin and tight junction Proteins. J Immunol. 2006;176(4):2161–2172.
  • Wikstrom ME, Stumbles PA. Mouse respiratory tract dendritic cell subsets and the immunological fate of inhaled antigens. Immunol Cell Biol. 2007;85(3):182–188.
  • Diebold SS, Kaisho T, Hemmi H, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303(5663):1529–1531.
  • Lund JM, Alexopoulou L, Sato A, et al. Recognition of single-stranded RNA viruses by toll-like receptor 7. Proc Natl Acad Sci U S A. 2004;101(15):5598–5603.
  • Kim TS, Braciale TJ. Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8+ T cell responses. PLoS One. 2009;4(1):e4204.
  • Belz GT, Smith CM, Kleinert L, et al. Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus. Proc Natl Acad Sci U S A. 2004;101(23):8670–8675.
  • Waithman J, Zanker D, Xiao K, et al. Resident CD8+ and migratory <sup>CD103+ dendritic cells control CD8 T cell immunity during acute influenza infection. PLoS One. 2013;8(6):e66136.
  • Ho AW, Prabhu N, Betts RJ, et al. Lung CD103 +dendritic cells efficiently transport influenza virus to the lymph node and load viral antigen onto MHC class I for presentation to CD8 T cells. J Immunol. 2011;187(11):6011–6021.
  • GeurtsvanKessel CH, Willart MA, van Rijt LS, et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b− but not plasmacytoid dendritic cells. J Exp Med. 2008;205(7):1621–1634.
  • Hao X, Kim TS, Braciale TJ, et al. Differential response of respiratory dendritic cell subsets to influenza virus infection. J Virol. 2008;82(10):4908–4919.
  • Sommereyns C, Paul S, Staeheli P, et al. IFN-λ (IFN-λ) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 2008;4(3):e1000017.
  • Broggi A, Ghosh S, Sposito B, et al. Type III interferons disrupt the lung epithelial barrier upon viral recognition. Science. 2020;369(6504):706–712.
  • Mordstein M, Kochs G, Dumoutier L, et al. Interferon-λ contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog. 2008;4(9):e1000151.
  • Mordstein M, Neugebauer E, Ditt V, et al. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol. 2010;84(11):5670–5677.
  • Major J, Crotta S, Llorian M, et al. Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. Science. 2020;369(6504):712–717.
  • Galani IE, Triantafyllia V, Eleminiadou EE, et al. Interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness. Immunity. 2017;46(5):875–90 e6.
  • Stetson DB, Medzhitov R. Type I interferons in host defense. Immunity. 2006;25(3):373–381.
  • Soloff AC, Weirback HK, Ross TM, et al. Plasmacytoid dendritic cell depletion leads to an enhanced mononuclear phagocyte response in lungs of mice with lethal influenza virus infection. Comp Immunol Microbiol Infect Dis. 2012;35(4):309–317.
  • Wolf AI, Buehler D, Hensley SE, et al. Plasmacytoid dendritic cells are dispensable during primary influenza virus infection. J Immunol. 2009;182(2):871–879.
  • Jing Y, Shaheen E, Drake RR, et al. Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Hum Immunol. 2009;70(10):777–784.
  • Shodell M, Siegal FP. Circulating, interferon-producing plasmacytoid dendritic cells decline during human ageing. Scand J Immunol. 2002;56(5):518–521.
  • Perez-Cabezas B, Naranjo-Gomez M, Fernandez MA, et al. Reduced numbers of plasmacytoid dendritic cells in aged blood donors. Exp Gerontol. 2007;42(10):1033–1038.
  • Canaday DH, Amponsah NA, Jones L, et al. Influenza-induced production of interferon-α is defective in geriatric individuals. J Clin Immunol. 2010;30(3):373–383.
  • Sridharan A, Esposo M, Kaushal K, et al. Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. Age (Dordr). 2011;33(3):363–376.
  • Agrawal A, Agrawal S, Cao JN, et al. Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J Immunol. 2007;178(11):6912–6922.
  • Prakash S, Agrawal S, Cao JN, et al. Impaired secretion of interferons by dendritic cells from aged subjects to influenza: role of histone modifications. Age (Dordr). 2013;35(5):1785–1797.
  • Franceschi C, Capri M, Monti D, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007;128(1):92–105.
  • Aksoy E, Saveanu L, Manoury B, et al. The isoform selective roles of PI3Ks in dendritic cell biology and function. Front Immunol. 2018;9:2574.
  • Camp JV, Jonsson CB. A role for neutrophils in viral respiratory disease. Front Immunol. 2017;8:550.
  • Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–1535.
  • Lim K, Hyun YM, Lambert-Emo K, et al. Neutrophil trails guide influenza-specific CD8+ T cells in the airways. Science. 2015;349(6252):aaa4352.
  • Hashimoto Y, Moki T, Takizawa T, et al. Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice. J Immunol. 2007;178(4):2448–2457.
  • Tate MD, Deng YM, Jones JE, et al. Neutrophils ameliorate lung injury and the development of severe disease during influenza infection. J Immunol. 2009;183(11):7441–7450.
  • Dienz O, Rud JG, Eaton SM, et al. Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung. Mucosal Immunol. 2012;5(3):258–266.
  • Wareing MD, Shea AL, Inglis CA, et al. CXCR2 is required for neutrophil recruitment to the lung during influenza virus infection, but is not essential for viral clearance. Viral Immunol. 2007;20(3):369–378.
  • Stadtmann A, Zarbock A. CXCR2: from bench to bedside. Front Immunol. 2012;3:263.
  • Perrone LA, Plowden JK, Garcia-Sastre A, et al. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 2008;4(8):e1000115.
  • Tang BM, Shojaei M, Teoh S, et al. Neutrophils-related host factors associated with severe disease and fatality in patients with influenza infection. Nat Commun. 2019;10(1):3422.
  • Zhu L, Liu L, Zhang Y, et al. High level of neutrophil extracellular traps correlates with poor prognosis of severe influenza A infection. J Infect Dis. 2018;217(3):428–437.
  • Dunning J, Blankley S, Hoang LT, et al. Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza. Nat Immunol. 2018;19(6):625–635.
  • Papayannopoulos V, Metzler KD, Hakkim A, et al. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol. 2010;191(3):677–691.
  • Metzler KD, Fuchs TA, Nauseef WM, et al. Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. Blood. 2011;117(3):953–959.
  • Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol. 2012;189(6):2689–2695.
  • Wenisch C, Patruta S, Daxbock F, et al. Effect of age on human neutrophil function. J Leukoc Biol. 2000;67(1):40–45.
  • Hazeldine J, Harris P, Chapple IL, et al. Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals. Aging Cell. 2014;13(4):690–698.
  • Vivier E, Tomasello E, Baratin M, et al. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–510.
  • Martin-Fontecha A, Thomsen LL, Brett S, et al. Induced recruitment of NK cells to lymph nodes provides IFN-γ for T(H)1 priming. Nat Immunol. 2004;5(12):1260–1265.
  • Hayakawa Y, Smyth MJ. CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J Immunol. 2006;176(3):1517–1524.
  • Chiossone L, Chaix J, Fuseri N, et al. Maturation of mouse NK cells is a 4-stage developmental program. Blood. 2009;113(22):5488–5496.
  • Kim S, Iizuka K, Kang HS, et al. In vivo developmental stages in murine natural killer cell maturation. Nat Immunol. 2002;3(6):523–528.
  • Huntington ND, Tabarias H, Fairfax K, et al. NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J Immunol. 2007;178(8):4764–4770.
  • Romagnani C, Juelke K, Falco M, et al. CD56 bright CD16 − killer Ig-like receptor −NK cells display longer telomeres and acquire features of CD56 dimNK cells upon activation. J Immunol. 2007;178(8):4947–4955.
  • Fu B, Wang F, Sun R, et al. CD11b and CD27 reflect distinct population and functional specialization in human natural killer cells. Immunology. 2011;133(3):350–359.
  • Marquardt N, Kekalainen E, Chen P, et al. Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69(-)CD56(dim) cells. J Allergy Clin Immunol. 2017;139(4):1321–30 e4.
  • Cooper GE, Ostridge K, Khakoo SI, et al. Human CD49a(+) lung natural killer cell cytotoxicity in response to influenza A virus. Front Immunol. 2018;9:1671.
  • Kumar P, Thakar MS, Ouyang W, et al. IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection. Mucosal Immunol. 2013;6(1):69–82.
  • Guo H, Topham DJ. Interleukin-22 (IL-22) production by pulmonary natural killer cells and the potential role of IL-22 during primary influenza virus infection. J Virol. 2010;84(15):7750–7759.
  • Guo H, Kumar P, Moran TM, et al. The functional impairment of natural killer cells during influenza virus infection. Immunol Cell Biol. 2009;87(8):579–589.
  • Mao H, Tu W, Qin G, et al. Influenza virus directly infects human natural killer cells and induces cell apoptosis. J Virol. 2009;83(18):9215–9222.
  • Hwang I, Scott JM, Kakarla T, et al. Activation mechanisms of natural killer cells during influenza virus infection. PLoS One. 2012;7(12):e51858.
  • Weiss ID, Wald O, Wald H, et al. IFN-γ treatment at early stages of influenza virus infection protects mice from death in a NK cell-dependent manner. J Interferon Cytokine Res. 2010;30(6):439–449.
  • Stein-Streilein J, Guffee J. In vivo treatment of mice and hamsters with antibodies to asialo GM1 increases morbidity and mortality to pulmonary influenza infection. J Immunol. 1986;136(4):1435–1441.
  • GeurtsvanKessel CH, Bergen IM, Muskens F, et al. Both conventional and interferon killer dendritic cells have antigen-presenting capacity during influenza virus infection. PLoS One. 2009;4(9):e7187.
  • Kos FJ, Engleman EG. Role of natural killer cells in the generation of influenza virus-specific cytotoxic T cells. Cell Immunol. 1996;173(1):1–6.
  • Fox A, Le NM, Horby P, et al. Severe pandemic H1N1 2009 infection is associated with transient NK and T deficiency and aberrant CD8 responses. PLoS One. 2012;7(2):e31535.
  • Denney L, Aitken C, Li CK, et al. Reduction of natural killer but not effector CD8 T lymphocytes in three consecutive cases of severe/lethal H1N1/09 influenza A virus infection. PLoS One. 2010;5(5):e10675.
  • Abdul-Careem MF, Mian MF, Yue G, et al. Critical role of natural killer cells in lung immunopathology during influenza infection in mice. J Infect Dis. 2012;206(2):167–177.
  • Zhou G, Juang SW, Kane KP, et al. NK cells exacerbate the pathology of influenza virus infection in mice. Eur J Immunol. 2013;43(4):929–938.
  • Yang H, Yogeeswaran G, Bukowski JF, et al. Expression of asialo GM1 and other antigens and glycolipids on natural killer cells and spleen leukocytes in virus-infected mice. Nat Immun Cell Growth Regul. 1985;4(1):21–39.
  • Moore ML, Chi MH, Goleniewska K, et al. Differential regulation of GM1 and asialo-GM1 expression by T cells and natural killer (NK) cells in respiratory syncytial virus infection. Viral Immunol. 2008;21(3):327–339.
  • Slifka MK, Pagarigan RR, Whitton JL, et al. NK markers are expressed on a high percentage of virus-specific CD8 + and CD4 + T cells. J Immunol. 2000;164(4):2009–2015.
  • Kambayashi T, Assarsson E, Michaelsson J, et al. Emergence of CD8 + T cells expressing NK cell receptors in influenza A virus-infected mice. J Immunol. 2000;165(9):4964–4969.
  • Liu B, Bao L, Wang L, et al. Anti-IFN-γ therapy alleviates acute lung injury induced by severe influenza A (H1N1) pdm09 infection in mice. J Microbiol Immunol Infect. 2019. DOI:10.1016/j.jmii.2019.07.009.
  • Mandelboim O, Lieberman N, Lev M, et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature. 2001;409(6823):1055–1060.
  • Gazit R, Gruda R, Elboim M, et al. Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat Immunol. 2006;7(5):517–523.
  • Draghi M, Pashine A, Sanjanwala B, et al. NKp46 and NKG2D recognition of infected dendritic cells is necessary for NK cell activation in the human response to influenza infection. J Immunol. 2007;178(5):2688–2698.
  • Thoren FB, Riise RE, Ousback J, et al. Human NK cells induce neutrophil apoptosis via an NKp46- and fas-dependent mechanism. J Immunol. 2012;188(4):1668–1674.
  • Beli E, Duriancik DM, Clinthorne JF, et al. Natural killer cell development and maturation in aged mice. Mech Ageing Dev. 2014;135:33–40.
  • Nair S, Fang M, Sigal LJ, et al. The natural killer cell dysfunction of aged mice is due to the bone marrow stroma and is not restored by IL-15/ IL-15Rα treatment. Aging Cell. 2015;14(2):180–190.
  • Zhang Y, Wallace DL, De Lara CM, et al. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology. 2007;121(2):258–265.
  • Hazeldine J, Lord JM. The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev. 2013;12(4):1069–1078.
  • Almeida-Oliveira A, Smith-Carvalho M, Porto LC, et al. Age-related changes in natural killer cell receptors from childhood through old age. Hum Immunol. 2011;72(4):319–329.
  • Hazeldine J, Hampson P, Lord JM, et al. Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell. 2012;11(5):751–759.
  • Chiu BC, Martin BE, Stolberg VR, et al. The host environment is responsible for aging-related functional NK cell deficiency. J Immunol. 2013;191(9):4688–4698.
  • Beli E, Clinthorne JF, Duriancik DM, et al. Natural killer cell function is altered during the primary response of aged mice to influenza infection. Mech Ageing Dev. 2011;132(10):503–510.
  • Moro K, Yamada T, Tanabe M, et al. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature. 2010;463(7280):540–544.
  • Mindt BC, Fritz JH, Duerr CU, et al. Group 2 innate lymphoid cells in pulmonary immunity and tissue homeostasis. Front Immunol. 2018;9:840.
  • Neill DR, Wong SH, Bellosi A, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464(7293):1367–1370.
  • Price AE, Liang HE, Sullivan BM, et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A. 2010;107(25):11489–11494.
  • Gasteiger G, Fan X, Dikiy S, et al. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science. 2015;350(6263):981–985.
  • De Grove KC, Provoost S, Hendriks RW, et al. Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses. J Allergy Clin Immunol. 2017;139(1):246–57 e4.
  • Ardain A, Porterfield JZ, Kloverpris HN, et al. Type 3 ILCs in lung disease. Front Immunol. 2019;10:92.
  • Lai DM, Shu Q, Fan J, et al. The origin and role of innate lymphoid cells in the lung. Mil Med Res. 2016;3:25.
  • Mjosberg JM, Trifari S, Crellin NK, et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol. 2011;12(11):1055–1062.
  • Entwistle LJ, Gregory LG, Oliver RA, et al. Pulmonary group 2 innate lymphoid cell phenotype is context specific: determining the effect of strain, Location, and stimuli. Front Immunol. 2019;10:3114.
  • Le Goffic R, Arshad MI, Rauch M, et al. Infection with influenza virus induces IL-33 in murine lungs. Am J Respir Cell Mol Biol. 2011;45(6):1125–1132.
  • Duerr CU, McCarthy CD, Mindt BC, et al. Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells. Nat Immunol. 2016;17(1):65–75.
  • Moro K, Kabata H, Tanabe M, et al. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat Immunol. 2016;17(1):76–86.
  • Godfrey DI, Uldrich AP, McCluskey J, et al. The burgeoning family of unconventional T cells. Nat Immunol. 2015;16(11):1114–1123.
  • Sabbaghi A, Miri SM, Keshavarz M, et al. Role of gamma delta T cells in controlling viral infections with a focus on influenza virus: implications for designing novel therapeutic approaches. Virol J. 2020;17(1):174.
  • van Wilgenburg B, Loh L, Chen Z, et al. MAIT cells contribute to protection against lethal influenza infection in vivo. Nat Commun. 2018;9(1):4706.
  • Juno JA, Keynan Y, Fowke KR, et al. Invariant NKT cells: regulation and function during viral infection. PLoS Pathog. 2012;8(8):e1002838.
  • Taylor RM. Experimental infection with influenza a virus in mice: the increase in intrapulmonary virus after inoculation and the influence of various factors thereon. J Exp Med. 1941;73(1):43–55.