The Proteolytic Activation of (H3N2) Influenza A Virus Hemagglutinin Is Facilitated by Different Type II Transmembrane Serine Proteases.
Bottom Line: In this study, we investigated an additional trypsin-like protease, TMPRSS4.Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus in vivo Influenza epidemics and recurring pandemics are responsible for significant global morbidity and mortality.Here we show that deletion of two host protease genes,Tmprss2 and Tmprss4, strongly reduced viral spread as well as lung pathology and resulted in increased survival after H3N2 virus infection.
Affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, and University of Veterinary Medicine Hannover, Braunschweig, Germany.Show MeSH
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Mentions: Both TMPRSS2 and TMPRSS4 are able to cleave H3 hemagglutinin in vitro and are expressed in influenza virus target cells. Therefore, we generated Tmprss2−/−Tmprss4−/− double-knockout mice and infected them with 2 × 103 FFU H3N2 virus. Indeed, infected double-mutant mice showed a delayed and significantly reduced loss of body weight compared to wild-type mice or Tmprss2−/− or Tmprss4−/− single-knockout mice (Fig. 4A). Furthermore, viral loads were significantly lower in double-knockout mice than in wild-type mice after infection with 2 × 103 FFU H3N2 virus at days 2 to 6 p.i. (Fig. 4B). In addition, the relative weight of wild-type lungs increased considerably more from days 2 to 6 postinfection than that of knockout lungs (Fig. 4C), indicating less infiltration of immune cells and accumulation of fluid. In agreement with these observations, the relative number of granulocytes in peripheral blood increased to higher levels in wild-type mice than in double-knockout mice after infection with H3N2 virus (Fig. 4D), which represents an indicator of severe influenza virus infection (28). However, both wild-type and knockout mice showed similar degrees of lymphopenia during the first 2 days p.i., followed by an increase of lymphocytes in both knockout and wild-type mice (Fig. 4D). Similar granulocytosis was observed in both strains on days 2 to 6 p.i.
Affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, and University of Veterinary Medicine Hannover, Braunschweig, Germany.