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.
Reading
Patrick C
PC
Department of Virology, Faculty of Medicine, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, UK.
Moore
Jeffrey B
JB
Smith
Geoffrey L
GL
D015096:3-Hydroxysteroid Dehydrogenases / Q000502:physiology*; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003602:Cytotoxicity, Immunologic; D005260:Female; D005938:Glucocorticoids / Q000502:physiology*; D007108:Immune Tolerance; D007249:Inflammation / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000821:virology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D014615:Vaccinia / Q000276:immunology*; D014616:Vaccinia virus / Q000201:enzymology* / Q000472:pathogenicity; D014764:Viral Proteins / Q000502:physiology*; D014774:Virulence; D014779:Virus Replication
D005938:Glucocorticoids; D014764:Viral Proteins; D007371:Interferon-gamma; D015096:3-Hydroxysteroid Dehydrogenases; D003345:Corticosterone