1887

Journal of General Virology header logo

Volume 99, Issue 9

Exchange of amino acids in the H1-haemagglutinin to H3 residues is required for efficient influenza A virus replication and pathology in Tmprss2 knock-out mice Open Access

Abstract

The haemagglutinin (HA) of H1N1 and H3N2 influenza A virus (IAV) subtypes has to be activated by host proteases. Previous studies showed that H1N1 virus cannot replicate efficiently in Tmprss2 knock-out mice whereas H3N2 viruses are able to replicate to the same levels in Tmprss2 as in wild type (WT) mice. Here, we investigated the sequence requirements for the HA molecule that allow IAV to replicate efficiently in the absence of TMPRSS2. We showed that replacement of the H3 for the H1-loop sequence (amino acids 320 to 329, at the C-terminus of HA1) was not sufficient for equal levels of virus replication or severe pathology in Tmprss2 knock-out mice compared to WT mice. However, exchange of a distant amino acid from H1 to H3 sequence (E31D) in addition to the HA-loop substitution resulted in virus replication in Tmprss2 knock-out mice that was comparable to WT mice. The higher virus replication and lung damage was associated with increased epithelial damage and higher mortality. Our results provide further evidence and insights into host proteases as a promising target for therapeutic intervention of IAV infections.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): hemagglutinin , host protease and influenza A virus
© 2018 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001128
2018-08-06
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/99/9/1187.html?itemId=/content/journal/jgv/10.1099/jgv.0.001128&mimeType=html&fmt=ahah

References

  1. Molinari NA, Ortega-Sanchez IR, Messonnier ML, Thompson WW, Wortley PM et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 2007; 25:5086–5096 [View Article][PubMed]
     [Google Scholar]
  2. Fauci AS. Seasonal and pandemic influenza preparedness: science and countermeasures. J Infect Dis 2006; 194:S73–S76 [View Article][PubMed]
     [Google Scholar]
  3. Wiley DC, Skehel JJ, Waterfield M. Evidence from studies with a cross-linking reagent that the haemagglutinin of influenza virus is a trimer. Virology 1977; 79:446–448 [View Article][PubMed]
     [Google Scholar]
  4. Bertram S, Glowacka I, Steffen I, Kühl A, Pöhlmann S. Novel insights into proteolytic cleavage of influenza virus hemagglutinin. Rev Med Virol 2010; 20:298–310 [View Article][PubMed]
     [Google Scholar]
  5. Garten W, Braden C, Arendt A, Peitsch C, Baron J et al. Influenza virus activating host proteases: identification, localization and inhibitors as potential therapeutics. Eur J Cell Biol 2015; 94:375–383 [View Article][PubMed]
     [Google Scholar]
  6. Kido H, Okumura Y, Yamada H, Le TQ, Yano M. Proteases essential for human influenza virus entry into cells and their inhibitors as potential therapeutic agents. Curr Pharm Des 2007; 13:405–414 [View Article][PubMed]
     [Google Scholar]
  7. Böttcher-Friebertshäuser E, Klenk HD, Garten W. Activation of influenza viruses by proteases from host cells and bacteria in the human airway epithelium. Pathog Dis 2013; 69:87–100 [View Article][PubMed]
     [Google Scholar]
  8. Bertram S, Glowacka I, Blazejewska P, Soilleux E, Allen P et al. TMPRSS2 and TMPRSS4 facilitate trypsin-independent spread of influenza virus in Caco-2 cells. J Virol 2010; 84:10016–10025 [View Article][PubMed]
     [Google Scholar]
  9. Böttcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W et al. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 2006; 80:9896–9898 [View Article][PubMed]
     [Google Scholar]
  10. Hatesuer B, Bertram S, Mehnert N, Bahgat MM, Nelson PS et al. Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice. PLoS Pathog 2013; 9:e1003774 [View Article][PubMed]
     [Google Scholar]
  11. Sakai K, Ami Y, Tahara M, Kubota T, Anraku M et al. The host protease TMPRSS2 plays a major role in in vivo replication of emerging H7N9 and seasonal influenza viruses. J Virol 2014; 88:5608–5616 [View Article][PubMed]
     [Google Scholar]
  12. Tarnow C, Engels G, Arendt A, Schwalm F, Sediri H et al. TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice. J Virol 2014; 88:4744–4751 [View Article][PubMed]
     [Google Scholar]
  13. Sakai K, Sekizuka T, Ami Y, Nakajima N, Kitazawa M et al. A mutant H3N2 influenza virus uses an alternative activation mechanism in TMPRSS2 knockout mice by loss of an oligosaccharide in the hemagglutinin stalk region. J Virol 2015; 89:5154–5158 [View Article][PubMed]
     [Google Scholar]
  14. Kühn N, Bergmann S, Kösterke N, Lambertz RLO, Keppner A et al. The proteolytic activation of (H3N2) influenza A virus hemagglutinin is facilitated by different type II transmembrane serine proteases. J Virol 2016; 90:4298–4307 [View Article][PubMed]
     [Google Scholar]
  15. Berman HM, Battistuz T, Bhat TN, Bluhm WF, Bourne PE et al. The Protein Data Bank. Acta Crystallogr D Biol Crystallogr 2002; 58:899–907 [View Article][PubMed]
     [Google Scholar]
  16. Stevens J, Corper AL, Basler CF, Taubenberger JK, Palese P et al. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science 2004; 303:1866–1870 [View Article][PubMed]
     [Google Scholar]
  17. Duhaut SD, Dimmock NJ. Defective segment 1 RNAs that interfere with production of infectious influenza A virus require at least 150 nucleotides of 5' sequence: evidence from a plasmid-driven system. J Gen Virol 2002; 83:403–411 [View Article][PubMed]
     [Google Scholar]
  18. Baron J, Tarnow C, Mayoli-Nüssle D, Schilling E, Meyer D et al. Matriptase, HAT, and TMPRSS2 activate the hemagglutinin of H9N2 influenza A viruses. J Virol 2013; 87:1811–1820 [View Article][PubMed]
     [Google Scholar]
  19. Gohrbandt S, Veits J, Breithaupt A, Hundt J, Teifke JP et al. H9 avian influenza reassortant with engineered polybasic cleavage site displays a highly pathogenic phenotype in chicken. J Gen Virol 2011; 92:1843–1853 [View Article][PubMed]
     [Google Scholar]
  20. Kawaoka Y, Naeve CW, Webster RG. Is virulence of H5N2 influenza viruses in chickens associated with loss of carbohydrate from the hemagglutinin?. Virology 1984; 139:303–316 [View Article][PubMed]
     [Google Scholar]
  21. Kollmus H, Wilk E, Schughart K. Systems biology and systems genetics - novel innovative approaches to study host-pathogen interactions during influenza infection. Curr Opin Virol 2014; 6:47–54 [View Article][PubMed]
     [Google Scholar]
  22. Short KR, Kroeze E, Fouchier RAM, Kuiken T. Pathogenesis of influenza-induced acute respiratory distress syndrome. Lancet Infect Dis 2014; 14:57–69 [View Article][PubMed]
     [Google Scholar]
  23. Crotta S, Davidson S, Mahlakoiv T, Desmet CJ, Buckwalter MR et al. Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia. PLoS Pathog 2013; 9:e1003773 [View Article][PubMed]
     [Google Scholar]
  24. Cheng Z, Zhou J, To KK, Chu H, Li C et al. Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A(H1N1) influenza and A(H7N9) influenza. J Infect Dis 2015; 212:1214–1221 [View Article][PubMed]
     [Google Scholar]
  25. Lazarowitz SG, Choppin PW. Enhancement of the infectivity of influenza A and B viruses by proteolytic cleavage of the hemagglutinin polypeptide. Virology 1975; 68:440–454 [View Article][PubMed]
     [Google Scholar]
  26. Garten W, Bosch FX, Linder D, Rott R, Klenk HD. Proteolytic activation of the influenza virus hemagglutinin: the structure of the cleavage site and the enzymes involved in cleavage. Virology 1981; 115:361–374 [View Article][PubMed]
     [Google Scholar]
  27. Böttcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W et al. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 2006; 80:9896–9898 Research Support, Non-U.S. Gov't [View Article][PubMed]
     [Google Scholar]
  28. Bertram S, Heurich A, Lavender H, Gierer S, Danisch S et al. Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts. PLoS One 2012; 7:e35876 [View Article][PubMed]
     [Google Scholar]
  29. Hamilton BS, Whittaker GR. Cleavage activation of human-adapted influenza virus subtypes by kallikrein-related peptidases 5 and 12. J Biol Chem 2013; 288:17399–17407 [View Article][PubMed]
     [Google Scholar]
  30. Zmora P, Blazejewska P, Moldenhauer AS, Welsch K, Nehlmeier I et al. DESC1 and MSPL activate influenza A viruses and emerging coronaviruses for host cell entry. J Virol 2014; 88:12087–12097 [View Article][PubMed]
     [Google Scholar]
  31. Magnen M, Elsässer BM, Zbodakova O, Kasparek P, Gueugnon F et al. Kallikrein-related peptidase 5 and seasonal influenza viruses, limitations of the experimental models for activating proteases. Biol Chem 2018 doi:10.1515/hsz-2017-0340 [View Article][PubMed]
     [Google Scholar]
  32. Kim TS, Heinlein C, Hackman RC, Nelson PS. Phenotypic analysis of mice lacking the Tmprss2-encoded protease. Mol Cell Biol 2006; 26:965–975 [View Article][PubMed]
     [Google Scholar]
  33. Li MZ, Elledge SJ. Harnessing homologous recombination in vitro to generate recombinant DNA via SLIC. Nat Methods 2007; 4:251–256 [View Article][PubMed]
     [Google Scholar]
  34. Hoffmann E, Neumann G, Kawaoka Y, Hobom G, Webster RG. A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci USA 2000; 97:6108–6113 [View Article][PubMed]
     [Google Scholar]
  35. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012; 9:671–675 [View Article][PubMed]
     [Google Scholar]
  36. R_Core_Team R: A Language and Environment for Statistical Computing Vienna, Austria: R Foundation for Statistical Computing; 2013 www.r-project.org/
     [Google Scholar]
  37. The_PyMOL_Molecular_Graphics_System, Version 1.8.2.3. Schrödinger, LLC:
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001128
Loading
Exchange of amino acids in the H1-haemagglutinin to H3 residues is required for efficient influenza A virus replication and pathology in Tmprss2 knock-out mice
J. Gen. Virol. 99, 1187 (2018); https://doi.org/10.1099/jgv.0.001128
/content/journal/jgv/10.1099/jgv.0.001128
/content/journal/jgv/10.1099/jgv.0.001128
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error