Isolation of the cellular protease that determines infectious tropism of influenza virus in human and inhibition of the infection by the protease inhibitor from human bronchial lavage

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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 of influenza A virus by tryptase Clara in vitro and in vivo. One is pulmonary surfactant which specifically inhibited tryptase Clara with a Ki value of 1.3 * 10^<-7> M but not other trypsin-type proteases, such as trypsin, factor Xa, plasmin and mast cell trytase. The other compound in the lavage was a 12kDa protein which was identified to be a human mucus protease inhibitor (MPI) by the amino acid sequence analysis. MPI inhibited the activity of tryptase Clara, with a Ki value of 9.7 * 10^<-8> M and multicycles of mouse-adopted influenza A virus replication in rat lungs in vivo. MPI consists of two homologous domains 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 compouds may be useful for the prevention and treatment of infection with influenza virus.