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: It was described previously that Tmprss2 is expressed in type 2 pneumocytes and bronchial epithelial cells (24), the main target cells for influenza A viruses (25, 26). TMPRSS4 is an additional protease with in vitro HA cleavage potential (10, 27). Therefore, we examined the expression profile of Tmprss4 in mouse lung tissues. We performed in situ hybridization (ISH) analyses to differentiate between type I and type II alveolar epithelial cells (AECI and AECII, respectively) in noninfected mouse lungs. As shown in Fig. 1A, round and mostly cuboidal AECII were detected by expression of the cell type-specific marker surfactant-associated protein C (Sftpc; stained blue). Thin and flat AECI could be identified by expression of the cell type-specific marker aquaporin 5 (Aqp5; stained red). In addition, we used immunohistochemical staining to detect expression of both TMPRSS2 and TMPRSS4. Staining could be observed in cuboidal and granular cells of alveolar tissue, representing AECII (Fig. 1B), as well as in the bronchiolar epithelium (Fig. 1C).
Affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, and University of Veterinary Medicine Hannover, Braunschweig, Germany.