[Frontiers in Bioscience 2, d588-591, December 1, 1997]

Table of Conents
 Previous Section   Next Section


M. Tashiro1 and J.T. Seto2

1 Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan, 162 and 2 Department of Microbiology, California State University, Los Angeles, Los Angeles, California, 90032-8201

Received 11/10/97 Accepted 11/14/97


The focus of our investigations has been on the molecular biology of the pathogenesis of paramyxoviruses,more specifically on the role of proteolytic cleavage of the viral glycoproteins. Host and organ tropism, spread of infection in the organism, and pathogenesis of paramyxoviruses have been well documented to be correlated with cleavage activation of the viral glycoproteins, and the host protease dependent expression of viral pathogenicity (1,2).

Sendai virus, the prototype of paramyxovirus, is a counterpart of human parainfluenza virus type 1 (HPIV1), which causes a respiratory infection in children. Sendai virus, isolated during an investigation of an outbreak of pneumonitis of the newborn (3), is exclusively pneumotropic in mice and readily establishes persistent infections in tissue cultures. Sendai virus has been used as a model for investigations on the in vivo mechanism of protease-mediated infections of respiratory agents (2).

Sendai virus has two glycoproteins, HN and F proteins. HN is for attachment of virus to cellular receptors and F is for cell fusion. Post-translational proteolytic cleavage of Fo into F1 and F2 subunits is essential for cell fusion, penetration, and activation of infectivity (4,5). The cleavage site of F protein consists of a single arginine residue. It is cleavable in vitro by trypsin. In embryonated eggs, Sendai virus is readily propagated in the infectious form by the proteins activating protease shown to be a blood clotting factor Xa, a vitamin K-dependent serine protease of the prothrombin family. It is secreted by the lining of the epithelial membrane cells into the allantoic and amniotic cavities (6,7). In the respiratory organs of rodents, progeny viruses are produced in the activated form and multiple cycles of replication take place resulting in extensive pathological damage in the lung. Tryptase Clara, a tryspin-like serine protease, has been identified in Clara cells, a secretory non-ciliated cell present in the bronchial and bronchiolar epithelium. Tryptase Clara has been shown to be a host protease that cleaves behind the single arginine residue at the site of cleavage of the F glycoprotein (8,9).

We proposed, that during long term persistent infections by paramyxoviruses, crisis or the fatal form of the disease may occur owing to the selection pressures that result in the preferential growth of protease activation mutants (10). Such a temperature sensitive (ts) host range mutant, ts-f1, has been isolated from persistently infected MDCK cells (11). Another host range mutant was isolated from ts-f1; it has been designated F1-R and found to be pantropic or cause a systemic infection in mice (12).