The Effects of Serpin Gene Mutations on the Distinctive Pathobiology of Cowpox and Rabbitpox Virus Following Intranasal Inoculation of Balb/c Mice

Abstract

Intranasal infection of Balb/c mice with 10 6 plaque forming units (PFU) of wild-type cowpox virus (CPV) and rabbitpox virus (RPV) induced strikingly different pulmonary pathology despite nearly identical clinical signs of illness and LD 50. Intranasal infection with CPV induced severe peribronchial, peribronchiolar, and perivascular hemorrhage with a mixed inflammatory cell infiltrate, bronchial and bronchiolar epithelial cell hyperplasia with intracytoplasmic acidophilic inclusion bodies, and alveolar hemorrhage and edema. In contrast, infection with RPV induced a mixed peribronchial and peribronchiolar inflammatory cell infiltrate, multifocal areas of bronchiolar epithelial cell coagulation necrosis, alveolar edema, and a conspicuous absence of pulmonary hemorrhage. Viremia was not detected following CPV infection and only 1 of 11 mice had brain-associated virus at death. Mice infected with RPV exhibited a viremia 2-3 days after infection and all mice bed virus associated with the brain at death. Mice infected with viruses containing certain serine protease inhibitor (SPI) gene mutations (CPV ΔSPI-1, CPV ΔSPI-3, and RPV SPI-1 -) exhibited no difference in clinical disease manifestation when compared with those infected with wild-type viruses. However, inactivation of the SPI-2 gene in either CPV or RPV resulted in disease attenuation and alteration of pulmonary pathology. Mice infected with the CPV ΔSPI-2 mutant showed decreased pulmonary hemorrhage, reduced inflammation, and an absence of alveolar edema, while mice infected with the RPV ΔSPI-2 mutant had a marked increase in intrapulmonary inflammatory cells and only a transient viremia.