Discovery of the potentiating proteases for influenza virus infection and their inhibitors as defensive compounds

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Post-translational proteolytic cleavage of precursors of the envelope fusion glycoproteins of RNA viruses is indispensable for virus entry into host cells. It is widely known that the pathogenicity of mammalian and nonpathogenic avian influenza viruses, and Sendai virus is primarily determined by host cellular processing proteases in the respiratory tract, which proteolytically induce fusion of viral envelope glycoproteins, HA of influenza viruses, and F0 of Sendai virus with the plasma membrane of target cells, allowing the viral genome to enter the cytoplasm. In the period granted by this foundation, we found new members of protease in airway that, like tryptase Clara, can process influenza A virus hemagglutinin and Sendai virus envelope fusion glycoprotein. One was found in the epithelial cells of the upward divisions of bronchioles and identified to be a mini-plasmin. Mini-plasmin potentiated the replication of broad-spectrum influenza A viruses and Sendai virus, even that of the plasmin-insensitive influenza A virus strain. The other was found in the epithelial cells of alveolar of rat lungs and was identified to be an ectopic anionic pancreatic trypsin. Mucus protease inhibitor(MPI)in nasal liquids and bronchial lavage inhibited the activity of tryptase Clara and partly that of trypsin. Mini-plasmin was not inhibited by α1-antiplasmin and MPI.These findings indicate that there are several proteases potentiating the infectivity of influenza virus in different loci in airway and the infectivity of influenza virus is regulated by the balance between the amounts of these proteases and their inhibitors in airway.