Role of receptor specificity and membrane fusion activity of influenza viruses in host range, cell tropism and pathogenicity

Research area: Molecular Virology/Molecular Immunology

Humans can be infected by seasonal, pandemic, and zoonotic influenza A viruses (IAVs). The hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins of these viruses vary substantially depending on viral host species, evolutionary lineage, and strain. The long-term goal of the project is to characterize how this genetic variation affects viral replication, host range, and pathogenicity. During the first funding period, a large panel of fully characterized recombinant IAVs were generated and used to study effects of HA receptor specificity and membrane fusion activity on viral tropism to epithelial and endothelial cells and sensitivity to antiviral innate immune factors. The Matrosovich group found that the pH optimum of HA-mediated membrane fusion in specific IAVs affects their sensitivity to an interferon-induced antiviral state, and that the high pH fusion pH optimum seen in zoonotic H5N1 and H7N9 viruses is responsible for their enhanced tropism to human endothelial cells. Furthermore, the group discovered that adaptation of avian influenza viruses to pigs under natural conditions requires HA mutations that increase the fusion pH optimum. Finally, preliminary evidence was obtained to suggest a role of viral receptor specificity in IAV interactions with human alveolar macrophages and plasmacytoid dendritic cells.

Project-related publications of the principal investigators:

  • Gerlach T, Hensen L, Matrosovich T, Bergmann J, Winkler M, Peteranderl C, Klenk HD, Weber F, Herold S, Pöhlmann S, Matrosovich M. 2017. pH-optimum of hemagglutinin-mediated membrane fusion determines sensitivity of influenza A viruses to the interferon-induced antiviral state and IFITMs. J. Virol., accepted
  • Gambaryan AS, Matrosovich MN. 2015. What adaptive changes in hemagglutinin and neuraminidase are necessary for emergence of pandemic influenza virus from its avian precursor? Biochemistry (Moscow) 80:872-880.
  • Baumann J, Kouassi NM, Foni E, Klenk HD, Matrosovich M. 2015. H1N1 swine influenza viruses differ from avian precursors by a higher pH optimum of membrane fusion. J Virol 90:1569-1577.
  • Wendel I, Rubbenstroth D, Doedt J, Kochs G, Wilhelm J, Staeheli P, Klenk HD, Matrosovich M. 2015. The avian-origin PB1 gene segment facilitated replication and transmissibility of the H3N2/1968 pandemic influenza virus. J Virol 89:4170-4179.
  • Wendel I, Matrosovich M, Klenk HD. 2015. SnapShot: Evolution of Human Influenza A Viruses. Cell Host & Microbe 17:416-416.e411.
  • Heider A, Mochalova L, Harder T, Tuzikov A, Bovin N, Wolff T, Matrosovich M, Schweiger B. 2015. Alterations in hemagglutinin receptor-binding specificity accompany the emergence of highly pathogenic avian influenza viruses. J Virol 89:5395-5405.
  • Van Poucke S, Doedt J, Baumann J, Qiu Y, Matrosovich T, Klenk HD, Van Reeth K, Matrosovich M. 2015. Role of substitutions in the hemagglutinin in the emergence of the 1968 pandemic influenza virus. J Virol 89:12211-12216.
  • Bottcher-Friebertshauser E, Garten W, Matrosovich M, Klenk HD. 2014. The hemagglutinin: a determinant of pathogenicity. Curr Top Microbiol Immunol 385:3-34.
  • Linster M, Boheemen S, de Graaf M, Schrauwen EJA, Lexmond P, Manz B, Bestebroer TM, Baumann J, van Riel D, Rimmelzwaan GF, Osterhaus ADME, Matrosovich M, Fouchier RAM, Herfst S. 2014. Identification, characterization, and natural selection of mutations driving airborne transmission of A/H5N1 virus. Cell 157:329-339.
  • Hogner K, Wolff T, Pleschka S, Plog S, Gruber AD, Kalinke U, Walmrath HD, Bodner J, Gattenlohner S, Lewe-Schlosser P, Matrosovich M, Seeger W, Lohmeyer J, Herold S. 2013. Macrophage-expressed IFN-beta contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia. Plos Pathog 9:e1003188.
  • Van Poucke S, Uhlendorff J, Wang ZF, Billiau V, Nicholls J, Matrosovich M, Van Reeth K. 2013. Effect of receptor specificity of A/Hong Kong/1/68 (H3N2) influenza virus variants on replication and transmission in pigs. Influenza and Other Respiratory Viruses 7:151-159.
  • Matrosovich M, Herrler G, Klenk HD. 2013. Sialic Acid Receptors of Viruses. Top Curr Chem 20:20.
  • Kolesnikova L, Heck S, Matrosovich T, Klenk HD, Becker S, Matrosovich M. 2013. Influenza virus budding from the tips of cellular microvilli in differentiated human airway epithelial cells. Journal of General Virology 94:971-976.
  • Klenk HD, Garten W, Matrosovich M. 2013. Pathogenesis, p 157-172. In Webster RG (ed), Textbook of Influenza, 2nd Edition. Wiley-Blackwell, Chichester, West Sussex, UK.
  • Crusat M, Liu JF, Palma AS, Childs RA, Liu Y, Wharton SA, Lin YP, Coombs PJ, Martin SR, Matrosovich M, Chen Z, Stevens DJ, Hien VM, Thanh TT, Nhu LNT, Nguyet LA, Ha DQ, van Doorn HR, Hien TT, Conradt HS, Kiso M, Gamblin SJ, Chai WG, Skehel JJ, Hay AJ, Farrar J, de Jong MD, Feizi T. 2013. Changes in the hemagglutinin of H5N1 viruses during human infection – Influence on receptor binding. Virology 447:326-337.
  • Corman VM, Eickmann M, Landt O, Bleicker T, Brunink S, Eschbach-Bludau M, Matrosovich M, Becker S, Drosten C. 2013. Specific detection by real-time reverse-transcription PCR assays of a novel avian influenza A(H7N9) strain associated with human spillover infections in China. Eurosurveillance 18:10-16.
  • Gambaryan, A. S., T. Y. Matrosovich, J. Philipp, V. J. Munster, R. A. Fouchier, G. Cattoli, I. Capua, S. L. Krauss, R. G. Webster, J. Banks, N. V. Bovin, H. D. Klenk, and M. N. Matrosovich. 2012. Receptor-binding profiles of H7 subtype influenza viruses in different host species. J.Virol. 86:4370-4379.
  • Liu, Y., R. A. Childs, T. Matrosovich, S. Wharton, A. S. Palma, W. Chai, R. Daniels, V. Gregory, J. Uhlendorff, M. Kiso, H. D. Klenk, A. Hay, T. Feizi, and M. Matrosovich. 2010. Altered receptor specificity and cell tropism of D222G hemagglutinin mutants isolated from fatal cases of pandemic A(H1N1) 2009 influenza virus. J.Virol. 84:12069-12074.
  • Childs, R. A., A. S. Palma, S. Wharton, T. Matrosovich, Y. Liu, W. Chai, M. A. Campanero-Rhodes, Y. Zhang, M. Eickmann, M. Kiso, A. Hay, M. Matrosovich, and T. Feizi. 2009. Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray. Nat.Biotechnol. 27:797-799.
  • Ocana-Macchi, M., M. Bel, L. Guzylack-Piriou, N. Ruggli, M. Liniger, K. C. McCullough, Y. Sakoda, N. Isoda, M. Matrosovich, and A. Summerfield. 2009. Hemagglutinin-dependent tropism of H5N1 avian influenza virus for human endothelial cells. J.Virol. 83:12947-12955.
  • Matrosovich, M., T. Matrosovich, J. Uhlendorff, W. Garten, and H. D. Klenk. 2007. Avian-virus-like receptor specificity of the hemagglutinin impedes influenza virus replication in cultures of human airway epithelium. Virology. 361:384-390.
  • Gambaryan, A., S. Yamnikova, D. Lvov, A. Tuzikov, A. Chinarev, G. Pazynina, R. Webster, M. Matrosovich, and N. Bovin. 2005. Receptor specificity of influenza viruses from birds and mammals: new data on involvement of the inner fragments of the carbohydrate chain. Virology 334:276-283.
  • Matrosovich, M. N., T. Y. Matrosovich, T. Gray, N. A. Roberts, and H. D. Klenk. 2004. Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proc.Natl.Acad.Sci U.S.A 101:4620-4624.
  • Matrosovich, M., A. Tuzikov, N. Bovin, A. Gambaryan, A. Klimov, M. R. Castrucci, I. Donatelli, and Y. Kawaoka. 2000. Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. J Virol. 74:8502-8512.
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  • Heil, F., P. Ahmad-Nejad, H. Hemmi, H. Hochrein, F. Ampenberger, T. Gellert, H. Dietrich, G. Lipford, K. Takeda, S. Akira, H. Wagner, and S. Bauer. 2003. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 33:2987-97.
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  • Jurk, M., F. Heil, J. Vollmer, C. Schetter, A. M. Krieg, H. Wagner, G. Lipford, and S. Bauer. 2002. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:499.
  • Rutz, M., J. Metzger, T. Gellert, P. Luppa, G. B. Lipford, H. Wagner, and S. Bauer. 2004. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol 34:2541-50.