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Limited replication of influenza A virus in human mast cells

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Abstract

Mast cells are important in innate immunity and protective against certain bacterial infections. However, there is limited evidence that mast cells respond to viruses. As mast cells are abundant in mucosal tissues of the lung, they are in a prime location to detect and respond to influenza virus. In this study, we characterized for the first time the replication cycle of influenza A virus in human mast cells by measuring influenza A virus transcription, RNA replication, protein synthesis, and formation of infectious virus as compared to the replication cycle in epithelial cells. We detected the presence of influenza A viral genomic RNA transcription, replication, and protein synthesis in human mast cells and epithelial cells. However, there was no significant release of infectious influenza A virus from mast cells, whereas epithelial cells produce ~100-fold virus compared with the inoculating dose. We confirmed that influenza A virus infects human mast cells, begins to replicate, but the production of new virus is aborted. Thus, mast cells may lack critical factors essential for productive infection or there are intrinsic or inducible anti-influenza A mechanisms in mast cells.

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References

  1. Rothberg MB, Haessler SD, Brown RB. Complications of viral influenza. Am J Med. 2008;121(4):258–64.

    Article  PubMed  Google Scholar 

  2. Julkunen I, Melen K, Nyqvist M, Pirhonen J, Sareneva T, Matikainen S. Inflammatory responses in influenza A virus infection. Vaccine. 2000;19(Suppl 1):S32–7.

    Article  PubMed  CAS  Google Scholar 

  3. Wang JP, Kurt-Jones EA, Finberg RW. Innate immunity to respiratory viruses. Cell Microbiol. 2007;9(7):1641–6.

    Article  PubMed  CAS  Google Scholar 

  4. Boyce JA. Mast cells: beyond IgE. J Allergy Clin Immunol. 2003;111(1):24–32; quiz 3.

    Google Scholar 

  5. Galli SJ, Maurer M, Lantz CS. Mast cells as sentinels of innate immunity. Curr Opin Immunol. 1999;11(1):53–9.

    Article  PubMed  CAS  Google Scholar 

  6. Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol. 2004;4(10):787–99.

    Article  PubMed  CAS  Google Scholar 

  7. Sundstrom JB, Ellis JE, Hair GA, Kirshenbaum AS, Metcalfe DD, Yi H, et al. Human tissue mast cells are an inducible reservoir of persistent HIV infection. Blood. 2007;109(12):5293–300.

    Article  PubMed  CAS  Google Scholar 

  8. Clementsen P, Bisgaard H, Pedersen M, Permin H, Struve-Christensen E, Milman N, et al. Staphylococcus aureus and influenza A virus stimulate human bronchoalveolar cells to release histamine and leukotrienes. Agents Actions. 1989;27(1–2):107–9.

    Article  PubMed  CAS  Google Scholar 

  9. Dietrich N, Rohde M, Geffers R, Kroger A, Hauser H, Weiss S, et al. Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Proc Natl Acad Sci USA. 2010;107(19):8748–53.

    Article  PubMed  CAS  Google Scholar 

  10. St. John AL, Rathore AP, Yap H, Ng ML, Metcalfe DD, Vasudevan SG et al. Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance. Proc Natl Acad Sci USA. 2011;108(22):9190–5.

  11. Hu Y, Jin Y, Han D, Zhang G, Cao S, Xie J, et al. Mast cell-induced lung injury in mice infected with H5N1 influenza virus. J Virol. 2012;86(6):3347–56.

    Article  PubMed  CAS  Google Scholar 

  12. King CA, Marshall JS, Alshurafa H, Anderson R. Release of vasoactive cytokines by antibody-enhanced dengue virus infection of a human mast cell/basophil line. J Virol. 2000;74(15):7146–50.

    Article  PubMed  CAS  Google Scholar 

  13. King CA, Anderson R, Marshall JS. Dengue virus selectively induces human mast cell chemokine production. J Virol. 2002;76(16):8408–19.

    Article  PubMed  CAS  Google Scholar 

  14. Brown MG, McAlpine SM, Huang YY, Haidl ID, Al-Afif A, Marshall JS, et al. RNA sensors enable human mast cell anti-viral chemokine production and IFN-mediated protection in response to antibody-enhanced dengue virus infection. PLoS ONE. 2012;7(3):e34055.

    Article  PubMed  CAS  Google Scholar 

  15. Kulka M, Alexopoulou L, Flavell RA, Metcalfe DD. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol. 2004;114(1):174–82.

    Article  PubMed  CAS  Google Scholar 

  16. Yan N, Chen ZJ. Intrinsic antiviral immunity. Nat Immunol. 2012;13(3):214–22.

    Article  PubMed  CAS  Google Scholar 

  17. Kirshenbaum AS, Akin C, Wu Y, Rottem M, Goff JP, Beaven MA, et al. Characterization of novel stem cell factor responsive human mast cell lines LAD 1 and 2 established from a patient with mast cell sarcoma/leukemia; activation following aggregation of FcepsilonRI or FcgammaRI. Leuk Res. 2003;27(8):677–82.

    Article  PubMed  CAS  Google Scholar 

  18. Sekar Y, Moon TC, Slupsky CM, Befus AD. Protein tyrosine nitration of aldolase in mast cells: a plausible pathway in nitric oxide-mediated regulation of mast cell function. J Immunol. 2010;185(1):578–87.

    Article  PubMed  CAS  Google Scholar 

  19. Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13). Blood. 1999;94(7):2333–42.

    PubMed  CAS  Google Scholar 

  20. Moon TC, Lee E, Baek SH, Murakami M, Kudo I, Kim NS, et al. Degranulation and cytokine expression in human cord blood-derived mast cells cultured in serum-free medium with recombinant human stem cell factor. Mol Cells. 2003;16(2):154–60.

    PubMed  CAS  Google Scholar 

  21. Yoshimura T, Moon TC, St Laurent CD, Puttagunta L, Chung K, Wright E et al. Expression of nitric oxide synthases in leukocytes in nasal polyps. Ann Allergy Asthma Immunol. 2012;108(3):172–7.

    Google Scholar 

  22. Duta V, Duta F, Puttagunta L, Befus AD, Duszyk M. Regulation of basolateral Cl(-) channels in airway epithelial cells: the role of nitric oxide. J Membr Biol. 2006;213(3):165–74.

    Article  PubMed  Google Scholar 

  23. Cottey R, Rowe CA, Bender BS. Influenza virus. Curr Protoc Immunol. 2001;Chapter 19:Unit 19 1.

  24. Gaush CR, Smith TF. Replication and plaque assay of influenza virus in an established line of canine kidney cells. Appl Microbiol. 1968;16(4):588–94.

    PubMed  CAS  Google Scholar 

  25. Reed LJ, Muench H. A simple method of estimating fifty percent endpoints. Am J Hyg. 1938;27:493–7.

    Google Scholar 

  26. Brown EG, Bailly JE. Genetic analysis of mouse-adapted influenza A virus identifies roles for the NA, PB1, and PB2 genes in virulence. Virus Res. 1999;61(1):63–76.

    Article  PubMed  CAS  Google Scholar 

  27. Manicassamy B, Manicassamy S, Belicha-Villanueva A, Pisanelli G, Pulendran B, Garcia-Sastre A. Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus. Proc Natl Acad Sci USA. 2010;107(25):11531–6.

    Article  PubMed  CAS  Google Scholar 

  28. Cassidy LF, Lyles DS, Abramson JS. Synthesis of viral proteins in polymorphonuclear leukocytes infected with influenza A virus. J Clin Microbiol. 1988;26(7):1267–70.

    PubMed  CAS  Google Scholar 

  29. Lee SM, Dutry I, Peiris JS. Editorial: macrophage heterogeneity and responses to influenza virus infection. J Leukoc Biol. 2012;92(1):1–4.

    Article  PubMed  Google Scholar 

  30. Ioannidis LJ, Verity EE, Crawford S, Rockman SP, Brown LE. Abortive replication of influenza virus in mouse dendritic cells. J Virol. 2012;86(10):5922–5.

    Article  PubMed  CAS  Google Scholar 

  31. Ye ZP, Pal R, Fox JW, Wagner RR. Functional and antigenic domains of the matrix (M1) protein of influenza A virus. J Virol. 1987;61(2):239–46.

    PubMed  CAS  Google Scholar 

  32. Ye ZP, Baylor NW, Wagner RR. Transcription-inhibition and RNA-binding domains of influenza A virus matrix protein mapped with anti-idiotypic antibodies and synthetic peptides. J Virol. 1989;63(9):3586–94.

    PubMed  CAS  Google Scholar 

  33. Baudin F, Petit I, Weissenhorn W, Ruigrok RW. In vitro dissection of the membrane and RNP binding activities of influenza virus M1 protein. Virology. 2001;281(1):102–8.

    Article  PubMed  CAS  Google Scholar 

  34. Kaiser L, Fritz RS, Straus SE, Gubareva L, Hayden FG. Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. J Med Virol. 2001;64(3):262–8.

    Article  PubMed  CAS  Google Scholar 

  35. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. 1999;282(13):1240–6.

    Article  PubMed  CAS  Google Scholar 

  36. Li Y, Li L, Wadley R, Reddel SW, Qi JC, Archis C, et al. Mast cells/basophils in the peripheral blood of allergic individuals who are HIV-1 susceptible due to their surface expression of CD4 and the chemokine receptors CCR3, CCR5, and CXCR4. Blood. 2001;97(11):3484–90.

    Article  PubMed  CAS  Google Scholar 

  37. Burke SM, Issekutz TB, Mohan K, Lee PW, Shmulevitz M, Marshall JS. Human mast cell activation with virus-associated stimuli leads to the selective chemotaxis of natural killer cells by a CXCL8-dependent mechanism. Blood. 2008;111(12):5467–76.

    Article  PubMed  CAS  Google Scholar 

  38. Dakhama A, Lee YM, Ohnishi H, Jing X, Balhorn A, Takeda K et al. Virus-specific IgE enhances airway responsiveness on reinfection with respiratory syncytial virus in newborn mice. J Allergy Clin Immunol. 2009;123(1):138–45.

    Google Scholar 

  39. Marshall JS, King CA, McCurdy JD. Mast cell cytokine and chemokine responses to bacterial and viral infection. Curr Pharm Des. 2003;9(1):11–24.

    Article  PubMed  CAS  Google Scholar 

  40. Shirato K, Taguchi F. Mast cell degranulation is induced by A549 airway epithelial cell infected with respiratory syncytial virus. Virology. 2009;386(1):88–93.

    Article  PubMed  CAS  Google Scholar 

  41. Artuc M, Steckelings UM, Grutzkau A, Smorodchenko A, Henz BM. A long-term coculture model for the study of mast cell-keratinocyte interactions. J Invest Dermatol. 2002;119(2):411–5.

    Article  PubMed  CAS  Google Scholar 

  42. Hsieh FH, Sharma P, Gibbons A, Goggans T, Erzurum SC, Haque SJ. Human airway epithelial cell determinants of survival and functional phenotype for primary human mast cells. Proc Natl Acad Sci USA. 2005;102(40):14380–5.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Canadian Institutes of Health Research (CIHR). Candy W. Marcet is a recipient of the Walter and Jessie Boyd and Charles Scriver MD/PhD Studentship from CIHR. We thank Drs. Kevin P. Kane and Earl G. Brown for FluA virus (A/PR/8/34 strain) and rabbit antiserum to FluA, respectively, and Dr Yokananth Sekar for repeating Western blots shown in Fig. 5.

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Correspondence to A. Dean Befus.

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Marcet, C.W., St. Laurent, C.D., Moon, T.C. et al. Limited replication of influenza A virus in human mast cells. Immunol Res 56, 32–43 (2013). https://doi.org/10.1007/s12026-012-8377-4

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