Research area: Molecular Virology

Proteolytic activation of enveloped viruses including influenza A and B virus (IAV/IBV) and coronaviruses (CoV) by host cell proteases is crucial for virus infectivity. We previously demonstrated in vitro that the transmembrane serine protease 2 (TMPRSS2) cleaves influenza virus hemagglutinin possessing a monobasic cleavage site. Further studies by us and others revealed that TMPRSS2 is capable of activating many respiratory viruses. Recently, we identified TMPRSS2 as major activating protease of IAV of almost all 16 HA-subtypes in human and murine airway cells and of IBV in human lung. Having established the crucial role of TMPRSS2 in influenza virus activation in lower human airways we now want to validate its role in IAV/IBV activation in the human upper respiratory tract. Furthermore, we aim at investigating the tissue distribution and role of TMPRSS2 orthologues in IAV activation in chicken and ducks that are important IAV hosts.

Project-related publications of the investigator:

• Bestle D, Limburg H, Kruhl D, Harbig A, Stein DA, Moulton H, Matrosovich M, Abdelwhab EM, Stech J, Bottcher-Friebertshauser E. 2021. Hemagglutinins of Avian Influenza Viruses Are Proteolytically Activated by TMPRSS2 in Human and Murine Airway Cells. J Virol 95:e0090621.
• Harbig A, Mernberger M, Bittel L, Pleschka S, Schughart K, Steinmetzer T, Stiewe T, Nist A, Bottcher-Friebertshauser E. 2020. Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways. J Biol Chem 295:11388-11407.
• Bestle D, Heindl MR, Limburg H, Van Lam van T, Pilgram O, Moulton H, Stein DA, Hardes K, Eickmann M, Dolnik O, Rohde C, Klenk HD, Garten W, Steinmetzer T, Bottcher-Friebertshauser E. 2020. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Sci Alliance 3.
• Limburg H, Harbig A, Bestle D, Stein DA, Moulton HM, Jaeger J, Janga H, Hardes K, Koepke J, Schulte L, Koczulla AR, Schmeck B, Klenk HD, Bottcher-Friebertshauser E. 2019. TMPRSS2 Is the Major Activating Protease of Influenza A Virus in Primary Human Airway Cells and Influenza B Virus in Human Type II Pneumocytes. J Virol 93.
• Bottcher-Friebertshauser E. 2018. Membrane-Anchored Serine Proteases: Host Cell Factors in Proteolytic Activation of Viral Glycoproteins. In: Böttcher-Friebertshäuser E., Garten W., Klenk H. (eds) Activation of Viruses by Host Proteases. Springer, Cham, p.153-203.
• Tarnow C, Engels G, Arendt A, Schwalm F, Sediri H, Preuss A, Nelson PS, Garten W, Klenk HD, Gabriel G, Bottcher-Friebertshauser E. 2014. TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice. J Virol 88:4744-51.
• Baron J, Tarnow C, Mayoli-Nussle D, Schilling E, Meyer D, Hammami M, Schwalm F, Steinmetzer T, Guan Y, Garten W, Klenk HD, Bottcher-Friebertshauser E. 2013. Matriptase, HAT, and TMPRSS2 activate the hemagglutinin of H9N2 influenza A viruses. J Virol 87:1811-20.
• Bottcher-Friebertshauser E, Lu Y, Meyer D, Sielaff F, Steinmetzer T, Klenk HD, Garten W. 2012. Hemagglutinin activating host cell proteases provide promising drug targets for the treatment of influenza A and B virus infections. Vaccine 30:7374-80.
• Bottcher-Friebertshauser E, Stein DA, Klenk HD, Garten W. 2011. Inhibition of influenza virus infection in human airway cell cultures by an antisense peptide-conjugated morpholino oligomer targeting the hemagglutinin-activating protease TMPRSS2. J Virol 85:1554-62.
• Bottcher-Friebertshauser E, Freuer C, Sielaff F, Schmidt S, Eickmann M, Uhlendorff J, Steinmetzer T, Klenk HD, Garten W. 2010. Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors. J Virol 84:5605-14.
• Bottcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W, Matrosovich M. 2006. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 80:9896-8.