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Comparison of pro-inflammatory cytokine expression and cellular signal transduction in human macrophages infected with different influenza A viruses

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Abstract

Influenza A virus infection of macrophages and virus-induced pro-inflammatory gene expression are regarded to contribute to severity of influenza A virus-caused diseases. Although some data are available on cytokine production by influenza A virus-infected macrophages, systematic comparisons of the virus types are currently considered to be of high relevance in humans (pandemic H1N1/2009, seasonal H1N1, seasonal H3N2, highly pathogenic avian influenza H5N1) on pro-inflammatory potential, and relevant underlying cellular signalling events are missing. Here, we show that the infection of human monocyte-derived macrophages with pandemic H1N1/2009 (A/HH/01/2009), seasonal H1N1/1999 (A/New Caledonia/20/99), seasonal H3N2/2004 (A/California/7/2004) or highly pathogenic H5N1/2004 (A/Thailand/1(Kan-1)/04) results in similar infection rates. However, the investigated H1N1 strains caused delayed and decreased apoptosis in comparison with H3N2/2004 or H5N1/2004. Moreover, human macrophage infection with H3N2/2004 or H5N1/2004 but not with H1N1 viruses was associated with pronounced pro-inflammatory cytokine production and activation of relevant mitogen-activated protein kinase pathways as indicated by phosphorylation of p38, JNK and ERK 1/2. These findings are in line with clinical observations indicating enhanced disease severity in H3N2- or H5N1-infected patients compared to individuals infected with pandemic H1N1/2009 or seasonal H1N1.

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References

  1. Wright PF, Neumann G, Kawaoka Y (2007) Orthomyxoviruses. In: Knipe DM, Howley PM (eds) Fields virology, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 1691–1740

    Google Scholar 

  2. Michaelis M, Doerr HW, Cinatl J Jr (2009) Of chickens and men: avian influenza in humans. Curr Mol Med 9:131–151

    Article  CAS  PubMed  Google Scholar 

  3. Michaelis M, Doerr HW, Cinatl J Jr (2009) Novel swine-origin influenza A virus in humans: another pandemic knocking at the door. Med Microbiol Immunol 198:175–183

    Article  PubMed  Google Scholar 

  4. Michaelis M, Doerr HW, Cinatl J Jr (2009) An influenza A H1N1 virus revival—pandemic H1N1/09 virus. Infection 37:381–389

    Article  CAS  PubMed  Google Scholar 

  5. Sauerbrei A, Schmidt-Ott R, Hoyer H, Wutzler P (2009) Seroprevalence of influenza A and B in German infants and adolescents. Med Microbiol Immunol 198:93–101

    Article  PubMed  Google Scholar 

  6. Allwinn R, Geiler J, Berger A, Cinatl J, Doerr HW (2010) Determination of serum antibodies against swine-origin influenza A virus H1N1/09 by immunofluorescence, haemagglutination inhibition, and by neutralization tests: how is the prevalence rate of protecting antibodies in humans? Med Microbiol Immunol 199:117–121

    Article  CAS  PubMed  Google Scholar 

  7. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza, Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, Uyeki TM, Zaki SR, Hayden FG, Hui DS, Kettner JD, Kumar A, Lim M, Shindo N, Penn C, Nicholson KG (2010) Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med 362:1708–1719

    Article  PubMed  Google Scholar 

  8. Taubenberger JK, Morens DM (2006) 1918 influenza: the mother of all pandemics. Emerg Infect Dis 12:15–22

    PubMed  Google Scholar 

  9. Erlach KC, Böhm V, Knabe M, Deegen P, Reddehase MJ, Podlech J (2008) Activation of hepatic natural killer cells and control of liver-adapted lymphoma in the murine model of cytomegalovirus infection. Med Microbiol Immunol 197:167–178

    Article  CAS  PubMed  Google Scholar 

  10. Kitz R, Rose MA, Placzek K, Schulze J, Zielen S, Schubert R (2008) LPS inhalation challenge: a new tool to characterize the inflammatory response in humans. Med Microbiol Immunol 197:13–19

    Article  CAS  PubMed  Google Scholar 

  11. Ritter U, Lechner A, Scharl K, Kiafard Z, Zwirner J, Körner H (2008) TNF controls the infiltration of dendritic cells into the site of Leishmania major infection. Med Microbiol Immunol 197:29–37

    Article  PubMed  Google Scholar 

  12. Zhou J, Yang XQ, Fu Z, Zhao XD, Jiang LP, Wang LJ, Cui YX (2008) Increased pathogenesis and inflammation of airways from respiratory syncytial virus infection in T cell deficient nude mice. Med Microbiol Immunol 197:345–351

    Article  CAS  PubMed  Google Scholar 

  13. Hünig T, Lühder F, Elflein K, Gogishvili T, Fröhlich M, Guler R, Cutler A, Brombacher F (2010) CD28 and IL-4: two heavyweights controlling the balance between immunity and inflammation. Med Microbiol Immunol 199:239–246

    Article  PubMed  Google Scholar 

  14. de Pádua Queiroz L Jr, Mattos ME Jr, da Silva MF Jr, Silva CL (2010) TGF-beta and CD23 are involved in nitric oxide production by pulmonary macrophages activated by beta-glucan from Paracoccidioides brasiliensis. Med Microbiol Immunol 199:61–69

    Article  PubMed  Google Scholar 

  15. Saini A, Harjai K, Mohan H, Punia RP, Chhibber S (2010) Long-term flaxseed oil supplementation diet protects BALB/c mice against Streptococcus pneumoniae infection. Med Microbiol Immunol 199:27–34

    Article  CAS  PubMed  Google Scholar 

  16. 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

    Article  PubMed  Google Scholar 

  17. Maines TR, Szretter KJ, Perrone L, Belser JA, Bright RA, Zeng H, Tumpey TM, Katz JM (2008) Pathogenesis of emerging avian influenza viruses in mammals and the host innate immune response. Immunol Rev 225:68–84

    Article  CAS  PubMed  Google Scholar 

  18. Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JS (2002) Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360:1831–1837

    Article  CAS  PubMed  Google Scholar 

  19. Guan Y, Poon LL, Cheung CY, Ellis TM, Lim W, Lipatov AS, Chan KH, Sturm-Ramirez KM, Cheung CL, Leung YH, Yuen KY, Webster RG, Peiris JS (2004) H5N1 influenza: a protean pandemic threat. Proc Natl Acad Sci USA 101:8156–8161

    Article  CAS  PubMed  Google Scholar 

  20. Woo PC, Tung ET, Chan KH, Lau CC, Lau KP, Yuen KY (2010) Cytokine profiles induced by the novel swine-origin influenza A/H1N1 virus: implications on treatment strategies. J Infect Dis 201:346–353

    Article  CAS  PubMed  Google Scholar 

  21. Michaelis M, Geiler J, Klassert D, Doerr HW, Cinatl J Jr (2009) Infection of human retinal pigment epithelial cells with influenza A viruses. Invest Ophthalmol Vis Sci 50:5419–5425

    Article  PubMed  Google Scholar 

  22. Geiler J, Michaelis M, Naczk P, Leutz A, Langer K, Doerr HW, Cinatl J Jr (2010) N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochem Pharmacol 79:413–420

    Article  CAS  PubMed  Google Scholar 

  23. Osterlund P, Pirhonen J, Ikonen N, Rönkkö E, Strengell M, Mäkelä SM, Broman M, Hamming OJ, Hartmann R, Ziegler T, Julkunen I (2010) Pandemic H1N1 2009 influenza A virus induces weak cytokine responses in human macrophages and dendritic cells and is highly sensitive to the antiviral actions of interferons. J Virol 84:1414–1422

    Article  CAS  PubMed  Google Scholar 

  24. Mok CK, Lee DC, Cheung CY, Peiris M, Lau AS (2007) Differential onset of apoptosis in influenza A virus H5N1- and H1N1-infected human blood macrophages. J Gen Virol 88:1275–1278

    Article  CAS  PubMed  Google Scholar 

  25. Cinatl J Jr, Michaelis M, Doerr HW (2007) The threat of avian influenza A (H5N1). Part I: epidemiologic concerns and virulence determinants. Med Microbiol Immunol 196:181–190

    Article  PubMed  Google Scholar 

  26. McAuley JL, Chipuk JE, Boyd KL, Van De Velde N, Green DR, McCullers JA (2010) PB1–F2 proteins from H5N1 and 20th century pandemic influenza viruses cause immunopathology. PLoS Pathog 6:e1001014

    Article  PubMed  Google Scholar 

  27. Mok KP, Wong CH, Cheung CY, Chan MC, Lee SM, Nicholls JM, Guan Y, Peiris JS (2009) Viral genetic determinants of H5N1 influenza viruses that contribute to cytokine dysregulation. J Infect Dis 200:1104–1112

    Article  CAS  PubMed  Google Scholar 

  28. Perrone LA, Plowden JK, García-Sastre A, Katz JM, Tumpey TM (2008) H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lung and mice. PLoS Pathog 4:1000115

    Article  Google Scholar 

  29. Chan RW, Yuen KM, Yu WC, Ho CC, Nicholls JM, Peiris JS, Chan MC (2010) Influenza H5N1 and H1N1 virus replication and innate immune responses in bronchial epithelial cells are influenced by the state of differentiation. PLoS One 5:e8713

    Article  PubMed  Google Scholar 

  30. Ludwig S, Ehrhardt C, Neumeier ER, Kracht M, Rapp UR, Pleschka S (2001) Influenza virus-induced AP-1-dependent gene expression requires activation of the JNK signaling pathway. J Biol Chem 276:10990–10998

    Article  CAS  Google Scholar 

  31. Pleschka S, Wolff T, Ehrhardt C, Hobom G, Planz O, Rapp UR, Ludwig S (2001) Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat Cell Biol 3:301–305

    Article  CAS  PubMed  Google Scholar 

  32. Ludwig S, Planz O, Pleschka S, Wolff T (2003) Influenza-virus-induced signaling cascades: targets for antiviral therapy? Trends Mol Med 9:46–52

    Article  CAS  PubMed  Google Scholar 

  33. Ludwig S, Pleschka S, Planz O, Wolf T (2006) Ringing the alarm bells: signaling and apoptosis in influenza virus infected cells. Cell Microbiol 8:375–386

    Article  CAS  PubMed  Google Scholar 

  34. Marjuki H, Yen HL, Franks J, Webster RG, Pleschka S, Hoffmann E (2007) Higher polymerase activity of a human influenza virus enhances activation of the hemagglutinin-induced Raf/MEK/ERK signal cascade. Virol J 4:134

    Article  PubMed  Google Scholar 

  35. Kujime K, Hashimoto S, Gon Y, Shimizu K, Horie T (2000) p38 mitogen-activated protein kinase and c-jun-NH2-terminal kinase regulate RANTES production by influenza virus-infected human bronchial epithelial cells. J Immunol 164:3222–3228

    CAS  PubMed  Google Scholar 

  36. Mori I, Goshima F, Koshizuka T, Koide N, Sugiyama T, Yoshida T, Yokochi T, Nishiyama Y, Kimura Y (2003) Differential activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 mitogen-activated protein kinase signal transduction pathways pathways in the mouse brain upon infection with neurovirulent Influenza-A-Virus. J Gen Virol 84:2401–2408

    Article  CAS  PubMed  Google Scholar 

  37. Lee DC, Cheung CY, Law AH, Mok CK, Peiris M, Lau AS (2005) p38 mitogen-activated protein kinase-dependent hyperinduction of tumor necrosis factor alpha expression in response to avian influenza virus H5N1. J Virol 79:10147–10154

    Article  CAS  PubMed  Google Scholar 

  38. Uchide N, Ohyama K, Bessho T, Toyoda H (2005) Induction of proinflammatory cytokine gene expression and apoptosis in human chorion cells of fetal membranes by influenza virus infection: possible implications for maintenance and interruption of pregnancy during infection. Med Sci Monit 11:RA7–RA16

    CAS  PubMed  Google Scholar 

  39. Xing Z, Cardona CJ, Anunciacion J, Adams S, Dao N (2010) Roles of ERK MAPK in the regulation of proinflammatory and apoptotic responses in chicken macrophages infected with H9N2 avian influenza virus. J Gen Virol 91:343–351

    Article  CAS  PubMed  Google Scholar 

  40. Hui KP, Lee SM, Cheung CY, Ng IH, Poon LL, Guan Y, Ip NY, Lau AS, Peiris JS (2009) Induction of proinflammatory cytokines in primary human macrophages by influenza A virus (H5N1) is selectively regulated by IFN regulatory factor 3 and p38 MAPK. J Immunol 182:1088–1098

    CAS  PubMed  Google Scholar 

  41. Wu W, Booth JL, Duggan ES, Wu S, Patel KB, Coggeshall KM, Metcalf JP (2010) Innate immune response to H3N2 and H1N1 influenza virus infection in a human lung organ culture model. Virology 396:178–188

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Kerstin Euler, Christina Christina Matreux and Gesa Meincke for technical support. The work was supported by the EU grant Intranasal H5 vaccine (proposal no. 044512), by the Hilfe für krebskranke Kinder Frankfurt e.V. and by the Frankfurter Stiftung für krebskranke Kinder.

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  1. Institut für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Paul Ehrlich-Str. 40, 60596, Frankfurt am Main, Germany

    Janina Geiler, Martin Michaelis, Patchima Sithisarn & Jindrich Cinatl Jr.

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  1. Janina Geiler
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  2. Martin Michaelis
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  4. Jindrich Cinatl Jr.
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Correspondence to Jindrich Cinatl Jr..

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Geiler, J., Michaelis, M., Sithisarn, P. et al. Comparison of pro-inflammatory cytokine expression and cellular signal transduction in human macrophages infected with different influenza A viruses. Med Microbiol Immunol 200, 53–60 (2011). https://doi.org/10.1007/s00430-010-0173-y

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  • DOI: https://doi.org/10.1007/s00430-010-0173-y

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