Steroid Hormone Synthesis by Vaccinia Virus Suppresses the Inflammatory Response to Infection

The 3beta-hydroxysteroid dehydrogenase (3beta-HSD) isoenzymes play a key role in cellular steroid hormone synthesis. Vaccinia virus (VV) also synthesizes steroid hormones with a 3beta-HSD enzyme (v3beta-HSD) encoded by gene A44L. Here we examined the effects of v3beta-HSD in VV disease using wild-type (vA44L), deletion (vDeltaA44L), and revertant (vA44L-rev) viruses in a murine intranasal model. Loss of A44L was associated with an attenuated phenotype. Early (days 1-3) after infection with vDeltaA44L or control viruses the only difference observed between groups was the reduced corticosterone level in lungs and plasma of vDeltaA44L-infected animals. Other parameters examined (body weight, signs of illness, temperature, virus titres, the pulmonary inflammatory infiltrate, and interferon [IFN]-gamma levels) were indistinguishable between groups. Subsequently, vDeltaA44L-infected animals had reduced weight loss and signs of illness, and displayed a vigorous pulmonary inflammatory response. This was characterized by rapid recruitment of CD4+ and CD8+ lymphocytes, enhanced IFN-gamma production and augmented cytotoxic T lymphocyte activity. These data suggest that steroid production by v3beta-HSD contributes to virus virulence by inhibiting an effective inflammatory response to infection.