Synergistic role of staphylococcal proteases in the induction of influenza virus pathogenicity

Several strains of Staphylococcus aureus have been found to secrete proteases that activate infectivity of influenza virus by proteolytic cleavage of the hemagglutinin. The enzymes of the bacterial strains Wood 46 and M 86/86 have been characterized in some detail and were found to be serine proteases. In their substrate specificities and inhibitor sensitivities they proved to be similar to, but not identical with trypsin and plasmin. The hemagglutinin of an individual virus strain could be cleaved by the proteases of some but not all staphylococcal strains, and a given enzyme could cleave only some but not all hemagglutinins analyzed. When mice were coinfected intranasally with the appropriate strains of influenza virus and S. aureus, the hemagglutinin was readily activated allowing multiple cycles of virus replication in the lung. Under these conditions, the animals came down with a fatal disease exhibiting extended lesions in the lung tissue. In contrast, after infection with virus or bacteria alone, there were no significant pathological changes. When the staphylococcal strain did not contain a protease that was able to activate the hemagglutinin of the coinfecting virus strain, the animals did not exhibit disease. These observations demonstrate that coinfecting bacteria can play an essential role in the development of influenza pneumonia by providing a protease suitable for cleavage activation of the hemagglutinin.