Abstract
Within days after infection, natural killer (NK) cells are recruited to the lungs and play an essential role in the immune response against influenza infection. Through interactions with the virus itself, as well as viral-infected cells, NK cells secrete a variety of cytokines and can contain viral replication by killing infected cells early after influenza infection. However, the virus has means of evading NK cell responses, including escaping NK cell recognition through mutation of the viral hemagglutinin (HA) protein, regulating HA levels, and by directly infecting and destroying NK cells. Although much of our understanding of NK cell role in influenza infection has come from animal models, there is increasing information from human infection. Studies conducted during the 2009 H1N1 pandemic provided much needed information on the importance of NK cells during human infection and suggest that NK lymphopenia may correlate with increased disease severity. However, more information on how different influenza virus subtypes influence NK cell levels and activities, the role of the different NK cell receptors in infection, and the impact of NK cells on human infection, particularly in high risk populations is needed.
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Abbreviations
- Dpi:
-
Days post-infection
- HA:
-
Hemagglutinin
- HPAI:
-
Highly pathogenic avian influenza
- IFN:
-
Interferon
- KIR:
-
Killer immunoglobulin-like receptor
- LPAI:
-
Low pathogenic avian influenza
- NA:
-
Neuraminidase
- NCR:
-
Natural cytotoxicity receptor
- NK:
-
Natural Killer
- PBMC:
-
Peripheral blood mononuclear cell
- PR8:
-
A/Puerto Rico/8/34 virus
- Th2:
-
T helper type-2
References
Abdul-Careem MF, Mian MF, Yue G, Gillgrass A, Chenoweth MJ, Barra NG, Chew MV, Chan T, Al-Garawi AA, Jordana M, Ashkar AA (2012) Critical role of natural killer cells in lung immunopathology during influenza infection in mice. J Infect Dis 206:167–177. doi:10.1093/infdis/jis340
Achdout H, Meningher T, Hirsh S, Glasner A, Bar-On Y, Gur C, Porgador A, Mendelson M, Mandelboim M, Mandelboim O (2010) Killing of avian and Swine influenza virus by natural killer cells. J Virol 84:3993–4001. doi:10.1128/JVI.02289-09
Ali SA, Rees RC, Oxford J (1984) Modulation of human natural killer cytotoxicity by influenza virus and its subunit protein. Immunology 52:687–695
Alter G, Malenfant JM, Altfeld M (2004) CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods 294:15–22. doi:10.1016/j.jim.2004.08.008
Altfeld M, Fadda L, Frleta D, Bhardwaj N (2011) DCs and NK cells: critical effectors in the immune response to HIV-1. Nat Rev Immunol 11:176–186. doi:10.1038/nri2935
Arnon TI, Achdout H, Lieberman N, Gazit R, Gonen-Gross T, Katz G, Bar-Ilan A, Bloushtain N, Lev M, Joseph A, Kedar E, Porgador A, Mandelboim O (2004) The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46. Blood 103:664–672. doi:10.1182/blood-2003-05-1716
Bar-On Y, Glasner A, Meningher T, Achdout H, Gur C, Lankry D, Vitenshtein A, Meyers AFA, Mandelboim M, Mandelboim O (2013) Neuraminidase-mediated, NKp46-dependent immune-evasion mechanism of influenza viruses. Cell Rep 3:1044–1050. doi:10.1016/j.celrep.2013.03.034
Bar-On Y, Seidel E, Tsukerman P, Mandelboim M, Mandelboim O (2014) Influenza virus uses its neuraminidase protein to evade the recognition of two activating NK cell receptors. J Infect Dis. doi:10.1093/infdis/jiu094
Beli E, Clinthorne JF, Duriancik DM, Hwang I, Kim S, Gardner EM (2011) Natural killer cell function is altered during the primary response of aged mice to influenza infection. Mech Ageing Dev 132:503–510
Bjorkstrom NK, Ljunggren HG, Sandberg JK (2010) CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol 31:401–406. doi:10.1016/j.it.2010.08.003
Clinthorne JF, Beli E, Duriancik DM, Gardner EM (2013) NK cell maturation and function in C57BL/6 mice are altered by caloric restriction. J Immunol 190:712–722. doi:10.4049/jimmunol.1201837
Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM (2009) Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci USA 106:1915–1919. doi:10.1073/pnas.0813192106
Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA (2001) Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 97:3146–3151
Culley FJ (2009) Natural killer cells in infection and inflammation of the lung. Immunology 128:151–163. doi:10.1111/j.1365-2567.2009.03167.x
Doherty PC, Turner SJ, Webby RG, Thomas PG (2006) Influenza and the challenge for immunology. Nat Immunol 7:449–455. doi:10.1038/ni1343
Dong L, Mori I, Hossain MJ, Kimura Y (2000) The senescence-accelerated mouse shows aging-related defects in cellular but not humoral immunity against influenza virus infection. J Infect Dis 182:391–396. doi:10.1086/315727
Fox A, Le NM, Horby P, van Doorn HR, Nguyen VT, Nguyen HH, Nguyen TC, Vu DP, Nguyen MH, Diep NT, Bich VT, Huong HT, Taylor WR, Farrar J, Wertheim H, Nguyen VK (2012) Severe pandemic H1N1 2009 infection is associated with transient NK and T deficiency and aberrant CD8 responses. PLoS One 7:e31535. doi:10.1371/journal.pone.0031535
Gardner EM (2005) Caloric restriction decreases survival of aged mice in response to primary influenza infection. J Gerontol A Biol Sci Med Sci 60:688–694
Gazit R, Gruda R, Elboim M, Arnon TI, Katz G, Achdout H, Hanna J, Qimron U, Landau G, Greenbaum E, Zakay-Rones Z, Porgador A, Mandelboim O (2006) Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat Immunol 7:517–523. doi:10.1038/ni1322
Ge N, Nishioka Y, Nakamura Y, Okano Y, Yoneda K, Ogawa H, Sugita A, Yanagawa H, Sone S (2004) Synthesis and secretion of interleukin-15 by freshly isolated human bronchial epithelial cells. Int Arch Allergy Immunol 135:235–242. doi:10.1159/000081309
Glasner A, Zurunic A, Meningher T, Lenac Rovis T, Tsukerman P, Bar-On Y, Yamin R, Meyers AF, Mandeboim M, Jonjic S, Mandelboim O (2012) Elucidating the mechanisms of influenza virus recognition by Ncr1. PloS One 7:e36837. doi:10.1371/journal.pone.0036837
Guo H, Kumar P, Malarkannan S (2011) Evasion of natural killer cells by influenza virus. J Leukoc Biol 89:189–194. doi:10.1189/jlb.0610319
Guo H, Topham DJ (2010) Interleukin-22 (IL-22) production by pulmonary natural Killer cells and the potential role of IL-22 during primary influenza virus infection. J Virol 84:7750–7759. doi:10.1128/JVI.00187-10
Hayakawa Y, Andrews DM, Smyth MJ (2010) Subset analysis of human and mouse mature NK cells. Methods Mol Biol 612:27–38. doi:10.1007/978-1-60761-362-6_3
Heltzer ML, Coffin SE, Maurer K, Bagashev A, Zhang Z, Orange JS, Sullivan KE (2009) Immune dysregulation in severe influenza. J Leukoc Biol 85:1036–1043. doi:10.1189/jlb.1108710
Ho JW, Hershkovitz O, Peiris M, Zilka A, Bar-Ilan A, Nal B, Chu K, Kudelko M, Kam YW, Achdout H, Mandelboim M, Altmeyer R, Mandelboim O, Bruzzone R, Porgador A (2008) H5-type influenza virus hemagglutinin is functionally recognized by the natural killer-activating receptor NKp44. J Virol 82:2028–2032. doi:10.1128/JVI.02065-07
Jansen CA, de Geus ED, van Haarlem DA, van de Haar PM, Londt BZ, Graham SP, Gobel TW, van Eden W, Brookes SM, Vervelde L (2013) Differential lung NK cell responses in avian influenza virus infected chickens correlate with pathogenicity. Sci Rep 3:2478. doi:10.1038/srep02478
Jost S, Altfeld M (2013) Control of human viral infections by natural killer cells. Annu Rev Immunol 31:163–194. doi:10.1146/annurev-immunol-032712-100001
Jost S, Quillay H, Reardon J, Peterson E, Simmons RP, Parry BA, Bryant NN, Binder WD, Altfeld M (2011) Changes in cytokine levels and NK cell activation associated with influenza. PLoS One 6:e25060. doi:10.1371/journal.pone.0025060
Juarez-Reyes A, Noyola DE, Monsivais-Urenda A, Alvarez-Quiroga C, Gonzalez-Amaro R (2013) Influenza virus infection but not H1N1 influenza virus immunization is associated with changes in peripheral blood NK cell subset levels. Clin Vaccine Immunol 20:1291–1297. doi:10.1128/CVI.00194-13
Kumar P, Thakar MS, Ouyang W, Malarkannan S (2013) IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection. Mucosal Immunol 6:69–82. doi:10.1038/mi.2012.49
La D, Czarnecki C, El-Gabalawy H, Kumar A, Meyers AF, Bastien N, Simonsen JN, Plummer FA, Luo M (2011) Enrichment of variations in KIR3DL1/S1 and KIR2DL2/L3 among H1N1/09 ICU patients: an exploratory study. PLoS One 6:e29200. doi:10.1371/journal.pone.0029200
Li J, Li H, Mao H, Yu M, Yang F, Feng T, Fan Y, Lu Q, Shen C, Yin Z, Mao M, Tu W (2013) Impaired NK cell antiviral cytokine response against influenza virus in small-for-gestational-age neonates. Cell Mol Immunol 10:437–443. doi:10.1038/cmi.2013.31
Liu B, Mori I, Hossain MJ, Dong L, Takeda K, Kimura Y (2004) Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated cytotoxicity. J Gen Virol 85:423–428
Manicassamy B, Manicassamy S, Belicha-Villanueva A, Pisanelli G, Pulendran B, Garcia-Sastre A (2010) Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus. Proc Natl Acad Sci USA 107:11531–11536. doi:10.1073/pnas.0914994107
Mao H, Tu W, Liu Y, Qin G, Zheng J, Chan PL, Lam KT, Peiris JS, Lau YL (2010) Inhibition of human natural killer cell activity by influenza virions and hemagglutinin. J Virol 84:4148–4157. doi:10.1128/JVI.02340-09
Mao H, Tu W, Qin G, Law HK, Sia SF, Chan PL, Liu Y, Lam KT, Zheng J, Peiris M, Lau YL (2009) Influenza virus directly infects human natural killer cells and induces cell apoptosis. J Virol 83:9215–9222. doi:10.1128/JVI.00805-09
Mendelson M, Tekoah Y, Zilka A, Gershoni-Yahalom O, Gazit R, Achdout H, Bovin NV, Meningher T, Mandelboim M, Mandelboim O, David A, Porgador A (2010) NKp46 O-glycan sequences that are involved in the interaction with hemagglutinin type 1 of influenza virus. J Virol 84:3789–3797. doi:10.1128/JVI.01815-09
Nogusa S, Ritz BW, Kassim SH, Jennings SR, Gardner EM (2008) Characterization of age-related changes in natural killer cells during primary influenza infection in mice. Mech Ageing Dev 129:223–230. doi:10.1016/j.mad.2008.01.003
O’Brien KB, Schultz-Cherry S, Knoll LJ (2011) Parasite-mediated upregulation of NK cell-derived gamma interferon protects against severe highly pathogenic H5N1 influenza virus infection. J Virol 85:8680–8688. doi:10.1128/JVI.05142-11
Owen RE, Yamada E, Thompson CI, Phillipson LJ, Thompson C, Taylor E, Zambon M, Osborn HM, Barclay WS, Borrow P (2007) Alterations in receptor binding properties of recent human influenza H3N2 viruses are associated with reduced natural killer cell lysis of infected cells. J Virol 81:11170–11178. doi:10.1128/JVI.01217-07
Pommerenke C, Wilk E, Srivastava B, Schulze A, Novoselova N, Geffers R, Schughart K (2012) Global transcriptome analysis in influenza-infected mouse lungs reveals the kinetics of innate and adaptive host immune responses. PLoS One 7:e41169. doi:10.1371/journal.pone.0041169
Ritz BW, Aktan I, Nogusa S, Gardner EM (2008) Energy restriction impairs natural killer cell function and increases the severity of influenza infection in young adult male C57BL/6 mice. J Nutr 138:2269–2275. doi:10.3945/jn.108.093633
Sato K, Iwai A, Nakayama Y, Morimoto J, Takada A, Maruyama M, Kida H, Uede T, Miyazaki T (2012) Osteopontin is critical to determine symptom severity of influenza through the regulation of NK cell population. Biochem Biophys Res Commun 417:274–279. doi:10.1016/j.bbrc.2011.11.100
Stein-Streilein J, Bennett M, Mann D, Kumar V (1983) Natural killer cells in mouse lung: surface phenotype, target preference, and response to local influenza virus infection. J Immunol 131:2699–2704
Stein-Streilein J, Guffee J (1986) In vivo treatment of mice and hamsters with antibodies to asialo GM1 increases morbidity and mortality to pulmonary influenza infection. J Immunol 136:1435–1441
Stein-Streilein J, Guffee J, Fan W (1988) Locally and systemically derived natural killer cells participate in defense against intranasally inoculated influenza virus. Reg Immunol 1:100–105
Sun JC, Beilke JN, Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457:557–561. doi:10.1038/nature07665
Toapanta FR, Ross TM (2009) Impaired immune responses in the lungs of aged mice following influenza infection. Respir Res 10:112. doi:10.1186/1465-9921-10-112
van Helden MJ, Zaiss DM, Sijts AJ (2012) CCR2 defines a distinct population of NK cells and mediates their migration during influenza virus infection in mice. PLoS One 7:e52027. doi:10.1371/journal.pone.0052027
Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S (2008) Functions of natural killer cells. Nat Immunol 9:503–510. doi:10.1038/ni1582
Walzer T, Blery M, Chaix J, Fuseri N, Chasson L, Robbins SH, Jaeger S, Andre P, Gauthier L, Daniel L, Chemin K, Morel Y, Dalod M, Imbert J, Pierres M, Moretta A, Romagne F, Vivier E (2007) Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proc Natl Acad Sci USA 104:3384–3389. doi:10.1073/pnas.0609692104
Wang J, Li F, Zheng M, Sun R, Wei H, Tian Z (2012) Lung natural killer cells in mice: phenotype and response to respiratory infection. Immunology 137:37–47. doi:10.1111/j.1365-2567.2012.03607.x
Weiss ID, Wald O, Wald H, Beider K, Abraham M, Galun E, Nagler A, Peled A (2010) IFN-gamma treatment at early stages of influenza virus infection protects mice from death in a NK cell-dependent manner. J Interferon Cytokine Res 30:439–449. doi:10.1089/jir.2009.0084
Zhou G, Juang SW, Kane KP (2013) NK cells exacerbate the pathology of influenza virus infection in mice. Eur J Immunol 43:929–938. doi:10.1002/eji.201242620
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Schultz-Cherry, S. (2014). Role of NK Cells in Influenza Infection. In: Oldstone, M., Compans, R. (eds) Influenza Pathogenesis and Control - Volume II. Current Topics in Microbiology and Immunology, vol 386. Springer, Cham. https://doi.org/10.1007/82_2014_403
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DOI: https://doi.org/10.1007/82_2014_403
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