Abstract
The influenza virus hemagglutinin (HA) facilitates viral entry into target cells. Cleavage of HA by host cell proteases is essential for viral infectivity, and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease (TTSP) TMPRSS2 has been identified as an HA activator in cell culture and in the infected host. However, it is less clear whether TMPRSS2-related enzymes can also activate HA for spread in target cells. Moreover, the activity of cellular serine protease inhibitors against HA-activating TTSPs is poorly understood. Here, we show that TMPRSS11A, another member of the TTSP family, cleaves and activates the influenza A virus (FLUAV) HA and the Middle East respiratory syndrome coronavirus spike protein (MERS-S). Moreover, we demonstrate that TMPRSS11A is expressed in murine tracheal epithelium, which is a target of FLUAV infection, and in human trachea, suggesting that the protease could support FLUAV spread in patients. Finally, we show that HA activation by the TMPRSS11A-related enzymes human airway tryptase and DESC1, but not TMPRSS11A itself, is blocked by the cellular serine protease inhibitor hepatocyte growth factor activator inhibitor type-1 (HAI-1). Our results suggest that TMPRSS11A could promote FLUAV spread in target cells and that HA-activating TTSPs exhibit differential sensitivity to blockade by cellular serine protease inhibitors.
Highlights
The influenza virus hemagglutinin (HA) facilitates viral entry into target cells
Our results suggest that TMPRSS11A could promote FLUAV spread in target cells and that HA-activating type II transmembrane serine protease (TTSP) exhibit differential sensitivity to blockade by cellular serine protease inhibitors
We show that TMPRSS11A cleaves and activates FLUAV HA and MERS coronavirus spike protein (MERS-S) and that endogenous TMPRSS11A is expressed in trachea, a target of FLUAV infection
Summary
Previous studies investigated the ability of diverse TTSPs to activate HA (9, 20 –23), TMPRSS11A, a member of the HAT/DESC subfamily of TTSPs, has so far not been examined To close this gap, we cloned the ORF of human TMPRSS11A and first analyzed protein expression in transfected 293T cells. In keeping with the cleavage analysis, coexpression of HAT, DESC1, and TMPRSS11A or treatment of cells with trypsin increased the spread of A/PR/8/34 (H1N1) or A/Panama/2007/1999 (H3N2) FLUAV (Fig. 2B). Coexpression of HAI-1 interfered with HA cleavage by HAT and DESC1 but not TMPRSS11A (Fig. 6A) In keeping with these results, HAI-1 expression inhibited FLUAV spread in cells transfected with HAT and DESC1 but not TMPRSS11A (Fig. 6B), whereas treatment with camostat mesylate, a serine protease inhibitor previously found to be active against TMPRSS2 [30, 31], blocked viral spread promoted by all three proteases (Fig. 6C). Autocatalytic activation of TMPRSS11A was not efficiently blocked by coexpression of HAI-1 (Fig. 7), indicating that HAI-1 can interfere with HA activation by some TTSPs but not others
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