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. 2017 Feb 23;32(2):122–129. doi: 10.1007/s12250-016-3918-y

Avian influenza virus directly infects human natural killer cells and inhibits cell activity

Huawei Mao 1,2,4,✉, Yinping Liu 2, Sin Fun Sia 3, J S Malik Peiris 3, Yu-Lung Lau 1,2,4, Wenwei Tu 2,✉
PMCID: PMC6598923  PMID: 28255852

Abstract

Natural killer (NK) cell is a key component of innate immunity and plays an important role in host defense against virus infection by directly destroying infected cells. Influenza is a respiratory disease transmitted in the early phase of virus infection. Evasion of host innate immunity including NK cells is critical for the virus to expand and establish a successful acute infection. Previously, we showed that human influenza H1N1 virus infects NK cells and induces cell apoptosis, as well as inhibits NK cell activity. In this study, we further demonstrated that avian influenza virus also directly targeted NK cells as an immunoevasion strategy. The avian virus infected human NK cells and induced cell apoptosis. In addition, avian influenza virion and HA protein inhibited NK cell cytotoxicity. This novel strategy has obvious advantages for avian influenza virus, allowing the virus sufficient time to expand and subsequent spread before the onset of the specific immune response. Our findings provide an important clue for the immunopathogenesis of avian influenza, and also suggest that direct targeting NK cells may be a common strategy used by both human and avian influenza viruses to evade NK cell immunity.

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Keywords: natural killer (NK) cell, avian influenza virus (AIV), immunoevasion, direction infection, inhibition, cytotoxicity

Acknowledgments

This work was supported in part by Theme-based Research Scheme (Project No. T11-705/14N), the General Research Fund (HKU 780113M, 17121214 and 17115015), Research Grants Council of the Hong Kong SAR, and Shenzhen Science and Technology Innovation Committee (JCYJ20140411175241066), China.

Footnotes

ORCID: 0000-0002-6801-8798

ORCID: 0000-0001-8807-9267

Contributor Information

Huawei Mao, Email: maohw@hku-szh.org.

Wenwei Tu, Email: wwtu@hku.hk.

References

  1. Abdel-Ghafar AN, Chotpitayasunondh T, Gao Z, Hayden FG, Nguyen D d, Jong MD, Naghdaliyev A, Peiris JS, Shindo N, Soeroso S, Uyeki TM. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med. 2008;358:261–273. doi: 10.1056/NEJMra0707279. [DOI] [PubMed] [Google Scholar]
  2. Achdout H, Manaster I, Mandelboim O. Influenza virus infection augments NK cell inhibition through reorganization of major histocompatibility complex class I proteins. J Virol. 2008;82:8030–8037. doi: 10.1128/JVI.00870-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arnon TI, Achdout H, Levi O, Markel G, Saleh N, Katz G, Gazit R, Gonen-Gross T, Hanna J, Nahari E, Porgador A, Honigman A, Plachter B, Mevorach D, Wolf DG, Mandelboim O. Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat Immunol. 2005;6:515–523. doi: 10.1038/ni1190. [DOI] [PubMed] [Google Scholar]
  4. 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. The mechanisms controlling the recognition of tumor-and virus-infected cells by NKp46. Blood. 2004;103:664–672. doi: 10.1182/blood-2003-05-1716. [DOI] [PubMed] [Google Scholar]
  5. Bar-On Y, Seidel E, Tsukerman P, Mandelboim M, Mandelboim O. Influenza virus uses its neuraminidase protein to evade the recognition of two activating NK cell receptors. J Infect Dis. 2014;210:410–418. doi: 10.1093/infdis/jiu094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chehimi J, Bandyopadhyay S, Prakash K, Perussia B, Hassan NF, Kawashima H, Campbell D, Kornbluth J, Starr SE. In vitro infection of natural killer cells with different human immunodeficiency virus type 1 isolates. J Virol. 1991;65:1812–1822. doi: 10.1128/jvi.65.4.1812-1822.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22:633–640. doi: 10.1016/s1471-4906(01)02060-9. [DOI] [PubMed] [Google Scholar]
  8. Crotta S, Stilla A, Wack A, D’Andrea A, Nuti S, D’Oro U, Mosca M, Filliponi F, Brunetto RM, Bonino F, Abrignani S, Valiante NM. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med. 2002;195:35–41. doi: 10.1084/jem.20011124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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, Hado Q, Guan Y, Peiris JS, Chinh NT, Hien TT, Farrar J. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12:1203–1207. doi: 10.1038/nm1477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Draghi M, Pashine A, Sanjanwala B, Gendzekhadze K, Cantoni C, Cosman D, Moretta A, Valiante NM, Parham P. NKp46 and NKG2D recognition of infected dendritic cells is necessary for NK cell activation in the human response to influenza infection. J Immunol. 2007;178:2688–2698. doi: 10.4049/jimmunol.178.5.2688. [DOI] [PubMed] [Google Scholar]
  11. Fernandez-Sesma A, Marukian S, Ebersole BJ, Kaminski D, Park MS, Yuen T, Sealfon SC, Garcia-Sastre A, Moran TM. Influenza virus evades innate and adaptive immunity via the NS1 protein. J Virol. 2006;80:6295–6304. doi: 10.1128/JVI.02381-05. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gambotto A, Barratt-Boyes SM, de Jong MD, Neumann G, Kawaoka Y. Human infection with highly pathogenic H5N1 influenza virus. Lancet. 2008;371:1464–1475. doi: 10.1016/S0140-6736(08)60627-3. [DOI] [PubMed] [Google Scholar]
  13. Guo H, Kumar P, Moran TM, Garcia-Sastre A, Zhou Y, Malarkannan S. The functional impairment of natural killer cells during influenza virus infection. Immunol Cell Biol. 2009;87:579–589. doi: 10.1038/icb.2009.60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Isobe Y, Sugimoto K, Yang L, Tamayose K, Egashira M, Kaneko T, Takada K, Oshimi K. Epstein-Barr virus infection of human natural killer cell lines and peripheral blood natural killer cells. Cancer Res. 2004;64:2167–2174. doi: 10.1158/0008-5472.can-03-1562. [DOI] [PubMed] [Google Scholar]
  15. Jonjic S, Babic M, Polic B, Krmpotic A. Immune evasion of natural killer cells by viruses. Curr Opin Immunol. 2008;20:30–38. doi: 10.1016/j.coi.2007.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Katze MG, Fornek JL, Palermo RE, Walters KA, Korth MJ. Innate immune modulation by RNA viruses: emerging insights from functional genomics. Nat Rev Immunol. 2008;8:644–654. doi: 10.1038/nri2377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Li J, Li H, Mao H, Yu M, Yang F, Feng T, Fan Y, Lu Q, Shen C, Yin Z, Mao M, Tu W. Impaired NK cell antiviral cytokine response against influenza virus in small-for-gestationalage neonates. Cell Mol Immunol. 2013;10:437–443. doi: 10.1038/cmi.2013.31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lodoen MB, Lanier LL. Viral modulation of NK cell immunity. Nat Rev Microbiol. 2005;3:59–69. doi: 10.1038/nrmicro1066. [DOI] [PubMed] [Google Scholar]
  19. Lodoen MB, Lanier LL. Natural killer cells as an initial defense against pathogens. Curr Opin Immunol. 2006;18:391–398. doi: 10.1016/j.coi.2006.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mandelboim O, Lieberman N, Lev M, Paul L, Arnon TI, Bushkin Y, Davis DM, Strominger JL, Yewdell JW, Porgador A. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature. 2001;409:1055–1060. doi: 10.1038/35059110. [DOI] [PubMed] [Google Scholar]
  21. Mao H, Tu W, Liu Y, Qin G, Zheng J, Chan PL, Lam KT, Peiris JS, Lau YL. Inhibition of human natural killer cell activity by influenza virions and hemagglutinin. J Virol. 2010;84:4148–4157. doi: 10.1128/JVI.02340-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mao H, Tu W, Qin G, Law HK, Sia SF, Chan PL, Liu Y, Lam KT, Zheng J, Peiris M, Lau YL. Influenza virus directly infects human natural killer cells and induces cell apoptosis. J Virol. 2009;83:9215–9222. doi: 10.1128/JVI.00805-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD. Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proc Natl Acad Sci U S A. 2004;101:4620–4624. doi: 10.1073/pnas.0308001101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nguyen TH, Farrar J, Horby P. Person-to-person transmission of influenza A (H5N1) Lancet. 2008;371:1392–1394. doi: 10.1016/S0140-6736(08)60494-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Orange JS, Fassett MS, Koopman LA, Boyson JE, Strominger JL. Viral evasion of natural killer cells. Nat Immunol. 2002;3:1006–1012. doi: 10.1038/ni1102-1006. [DOI] [PubMed] [Google Scholar]
  26. Owen RE, Yamada E, Thompson CI, Phillipson LJ, Thompson C, Taylor E, Zambon M, Osborn HM, Barclay WS, Borrow P. Alterations in receptor binding properties of recent human influenza H3N2 viruses are associated with reduced natural killer cell lysis of infected cells. J Virol. 2007;81:11170–11178. doi: 10.1128/JVI.01217-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Parker AK, Yokoyama WM, Corbett JA, Chen N, Buller RM. Primary naive and interleukin-2-activated natural killer cells do not support efficient ectromelia virus replication. J Gen Virol. 2008;89:751–759. doi: 10.1099/vir.0.83205-0. [DOI] [PubMed] [Google Scholar]
  28. Peiris JS, Yu WC, Leung CW, Cheung CY, Ng WF, Nicholls JM, Ng TK, Chan KH, Lai ST, Lim WL, Yuen KY, Guan Y. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet. 2004;363:617–619. doi: 10.1016/S0140-6736(04)15595-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Peruzzi M, Azzari C, Rossi ME, De Martino M, Vierucci A. Inhibition of natural killer cell cytotoxicity and interferon gamma production by the envelope protein of HIV and prevention by vasoactive intestinal peptide. AIDS Res Hum Retroviruses. 2000;16:1067–1073. doi: 10.1089/08892220050075336. [DOI] [PubMed] [Google Scholar]
  30. Rogers GN, Pritchett TJ, Lane JL, Paulson JC. Differential sensitivity of human, avian, and equine influenza A viruses to a glycoprotein inhibitor of infection: selection of receptor specific variants. Virology. 1983;131:394–408. doi: 10.1016/0042-6822(83)90507-x. [DOI] [PubMed] [Google Scholar]
  31. Scalzo AA. Successful control of viruses by NK cells—a balance of opposing forces. Trends Microbiol. 2002;10:470–474. doi: 10.1016/s0966-842x(02)02441-1. [DOI] [PubMed] [Google Scholar]
  32. Spies T, Groh V. Natural cytotoxicity receptors: influenza virus in the spotlight. Nat Immunol. 2006;7:443–444. doi: 10.1038/ni0506-443. [DOI] [PubMed] [Google Scholar]
  33. Su S, Bi Y, Wong G, Gray GC, Gao GF, Li S. Epidemiology, Evolution, and Recent Outbreaks of Avian Influenza Virus in China. J Virol. 2015;89:8671–8676. doi: 10.1128/JVI.01034-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sun Y, Liu J. H9N2 influenza virus in China: a cause of concern. Protein Cell. 2015;6:18–25. doi: 10.1007/s13238-014-0111-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tam JS. Influenza A (H5N1) in Hong Kong: an overview. Vaccine. 2002;20(2):S77–S81. doi: 10.1016/s0264-410x(02)00137-8. [DOI] [PubMed] [Google Scholar]
  36. Thomas JK, Noppenberger J. Avian influenza: a review. Am J Health Syst Pharm. 2007;64:149–165. doi: 10.2146/ajhp060181. [DOI] [PubMed] [Google Scholar]
  37. Ungchusak K, Auewarakul P, Dowell SF, Kitphati R, Auwanit W, Puthavathana P, Uiprasertkul M, Boonnak K, Pittayawonganon C, Cox NJ, Zaki SR, Thawatsupha P, Chittaganpitch M, Khontong R, Simmerman JM, Chunsutthiwat S. Probable person-to-person transmission of avian influenza A (H5N1) N Engl J Med. 2005;352:333–340. doi: 10.1056/NEJMoa044021. [DOI] [PubMed] [Google Scholar]
  38. Van Kerkhove MD. Brief literature review for the WHO global influenza research agenda—highly pathogenic avian influenza H5N1 risk in humans. Influenza Other Respir Viruses. 2013;7(2):26–33. doi: 10.1111/irv.12077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wang H, Feng Z, Shu Y, Yu H, Zhou L, Zu R, Huai Y, Dong J, Bao C, Wen L, Wang H, Yang P, Zhao W, Dong L, Zhou M, Liao Q, Yang H, Wang M, Lu X, Shi Z, Wang W, Gu L, Zhu F, Li Q, Yin W, Yang W, Li D, Uyeki TM, Wang Y. Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China. Lancet. 2008;371:1427–1434. doi: 10.1016/S0140-6736(08)60493-6. [DOI] [PubMed] [Google Scholar]
  40. Webster RG, Govorkova EA. H5N1 influenza—continuing evolution and spread. N Engl J Med. 2006;355:2174–2177. doi: 10.1056/NEJMp068205. [DOI] [PubMed] [Google Scholar]
  41. WHO. Epidemiology of WHO-confirmed human cases of avian influenza A (H5N1) infection. Wkly Epidemiol Rec. 2006;81:249–257. [PubMed] [Google Scholar]
  42. WHO. Cumulative number of confirmed human cases for avian influenza A (H5N1) reported to WHO, 2003–2015. 2015. [Google Scholar]
  43. Yuen KY, Chan PK, Peiris M, Tsang DN, Que TL, Shortridge KF, Cheung PT, To WK, Ho ET, Sung R, Cheng AF. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet. 1998;351:467–471. doi: 10.1016/s0140-6736(98)01182-9. [DOI] [PubMed] [Google Scholar]
  44. Zhang KY, Zhu L, Bai JG, Han ZY, Guo HM, Zhang ZP, Zhu QY. Altered lymphocyte counts in a pediatric patient with H5N1 infection. Pediatr Emerg Care. 2012;28:921–923. doi: 10.1097/PEC.0b013e318267f419. [DOI] [PubMed] [Google Scholar]
  45. Zocchi MR, Rubartelli A, Morgavi P, Poggi A. HIV-1 Tat inhibits human natural killer cell function by blocking L-type calcium channels. J Immunol. 1998;161:2938–2943. [PubMed] [Google Scholar]

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