title: Strain-dependent requirement for IFN-γ for respiratory control and immunotherapy in murine gammaherpesvirus infection.
abstract: Interferon-γ (IFN-γ) and perforin (pfp) are important effector mechanisms used by CD8 T cells to clear virus-infected cells. In this study, we used IFN-γ/pfp double knockout mice to address if these two effector molecules play redundant roles in the control of acute infection with murine gammaherpesvirus-68 (MHV-68) in BALB/C mice. Perforin knockout (KO) mice and wild-type mice cleared infectious virus from the lungs, even following high-dose infection. However, the IFN-γ KO and IFN-γ/pfp double knockout (DKO) groups had higher virus titers in the lungs at day 10 post-infection, and both groups had higher mortality rates. In IFN-γ/pfp DKO mice, the virus titer and mortality rate were significant higher than in IFN-γ KO mice, indicating a role for perforin in protection from disease. WT mice given IFN-γ blocking antibody also showed significantly higher viral titers. In contrast, IFN-γ KO mice on a C57BL/6 background controlled respiratory infection comparably to wild-type mice. These data show that perforin plays a redundant role in the control of virus replication, but IFN-γ plays an essential role in BALB/C mice infected with MHV-68. We conclude that there is a marked strain-dependent difference in the effector mechanisms needed to control acute MHV-68 infection between C57BL/6 and BALB/C mice. In addition we show that immune therapy that re-establishes viral control after spontaneous reactivation in CD4-deficient mice depends upon perforin in C57BL/6 mice but IFN-γ in BALB/C mice.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Tsai
authors.forename: Zhuting
authors.initials: Z
authors.lastname: Hu
authors.forename: Weijun
authors.initials: W
authors.lastname: Zhang
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Usherwood
mesh_terms: D000818:Animals; D006566:Herpesviridae Infections / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin / Q000235:genetics / Q000276:immunology*; D012141:Respiratory Tract Infections / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D018144:Rhadinovirus / Q000472:pathogenicity*; D012376:Rodent Diseases / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D016019:Survival Analysis
chemical_list: D054353:Perforin; D007371:Interferon-gamma