6th International Influenza Meeting

Trypsin-like serine proteases in the lower respiratory tract of mice and their putative role in proteolytic activation of influenza A and B viruses

Not scheduled

15m

Oral presentation

Description

Cleavage of the hemagglutinin (HA) precursor protein into its subdomains by host cell proteases is essential for virus infectivity, spread and pathogenicity. Seasonal influenza A and B viruses possess a monobasic HA cleavage site with a single arginine and are activated by trypsin-like proteases. TMPRSS2, a type II transmembrane serine protease (TTSP), activates HA with monobasic cleavage site in vitro and turned out to be an essential host cell factor for pathogenicity of H7N9 and H1N1 in mice in vivo. Cleavage activation of H3N2 instead, is less dependent on TMPRSS2 and due to additional so far unknown trypsin-like protease(s). Activation of influenza B virus has been demonstrated to be independent on TMPRSS2 in mice, as well.
These results revealed that influenza viruses can vary in their sensitivity to different proteases and therefore exhibit diversified protease specificity. Here, we analyze the protease repertoire in airway tissues of the lower respiratory tract of mice (trachea, bronchi and lung) by RNA sequencing in order to screen for further HA activating proteases. Comparison of these data with expression profiles in immortalized mouse lung epithelial cells (MLE-15), a negative cell culture system for HA cleavage, enables evaluation of protease candidates. Based on transcriptomic data, selected protease candidates present in murine airways and but absent in MLE-15 cells were analyzed for HA activation in cell culture experiments. Identification of further HA activating proteases could lead to novel therapeutic targets for influenza treatment.