title: Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice.
abstract: Annual influenza epidemics and occasional pandemics pose a severe threat to human health. Host cell factors required for viral spread but not for cellular survival are attractive targets for novel approaches to antiviral intervention. The cleavage activation of the influenza virus hemagglutinin (HA) by host cell proteases is essential for viral infectivity. However, it is unknown which proteases activate influenza viruses in mammals. Several candidates have been identified in cell culture studies, leading to the concept that influenza viruses can employ multiple enzymes to ensure their cleavage activation in the host. Here, we show that deletion of a single HA-activating protease gene, Tmprss2, in mice inhibits spread of mono-basic H1N1 influenza viruses, including the pandemic 2009 swine influenza virus. Lung pathology was strongly reduced and mutant mice were protected from weight loss, death and impairment of lung function. Also, after infection with mono-basic H3N2 influenza A virus body weight loss and survival was less severe in Tmprss2 mutant compared to wild type mice. As expected, Tmprss2-deficient mice were not protected from viral spread and pathology after infection with multi-basic H7N7 influenza A virus. In conclusion, these results identify TMPRSS2 as a host cell factor essential for viral spread and pathogenesis of mono-basic H1N1 and H3N2 influenza A viruses.
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, University of Veterinary Medicine Hannover, Braunschweig, Germany, and University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hatesuer
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bertram
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, University of Veterinary Medicine Hannover, Braunschweig, Germany, and University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Nora
authors.initials: N
authors.lastname: Mehnert
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, University of Veterinary Medicine Hannover, Braunschweig, Germany, and University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Bahgat
authors.affiliation: Divisons of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Stefan
authors.initials: S
authors.lastname: Pöhlmann
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pöhlman
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, University of Veterinary Medicine Hannover, Braunschweig, Germany, and University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schughart
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D004285:Dogs; D005260:Female; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D053122:Influenza A Virus, H3N2 Subtype / Q000472:pathogenicity; D007251:Influenza, Human / Q000235:genetics / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000821:virology; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology*
chemical_list: D012697:Serine Endopeptidases; C000588699:TMPRSS2 protein, mouse