Virus activation by tryptase and its inhibition in vivo

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Tryptase Clara, a trypsin-like protease localized exclusively in and secreted from Clara cells of the bronchial epithelium proteolytically activates the infectivity of influenza A virus [H.Kido, Y.Yokogoshi, K.Sakai, M.Tashiro, Y.Kishino, A.Fukutomi and N.Katunuma (1992), J.Biol.Chem.267 : 13573-13579]. In this research project, we found two compounds in human bronchial ravage, which inhibited the proteolytic activation by tryptase Clara of influenza A virus in vitro and in vivo. One is pulmonary surfactant which specifically adsorbed tryptase Clara, resulting in its inactivation but not other trypsin-type proteases, such as trypsin, factor Xa, plasmin and mast cell tryptase. The other compound in the lavage was a 12kDa protein which was identified to be an antileukoprotease (ALP) by the amino acid sequence analysis. ALP inhibited the activity of tryptase Clara, with a Ki value of 9.7 x 10^<-8> M and multi-cycles of mouse-adopted influenza A virus replication in rat lungs in vivo. MPI consists of two homologous domins and the C-terminal domain inhibited the virus activation but the N-terminal domain had little effect. Taken together, we found two endogenous local defensive compounds which inhibit proteolytic activation of influenza A virus by tryptase Clara. These compounds may be useful for the prevention and treatment of infection with influenza virus.