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Updated: May 30, 2026
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Strain-dependent requirement for IFN-γ for respiratory control and immunotherapy in murine gammaherpesvirus infection
Ching-Yi Tsai1, Zhuting Hu, Weijun Zhang
1Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
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.
Insights
Interferon-gamma (IFN-γ) is essential for controlling murine gammaherpesvirus-68 (MHV-68) in BALB/C mice, while perforin plays a redundant role. Strain differences impact immune control mechanisms.
Area of Science:
- Immunology
- Virology
- Infectious Disease
Background:
- CD8 T cells utilize Interferon-gamma (IFN-γ) and perforin (pfp) to eliminate virus-infected cells.
- Murine gammaherpesvirus-68 (MHV-68) is a model for studying T cell-mediated viral control.
Purpose of the Study:
- To investigate the redundant or essential roles of IFN-γ and perforin in controlling acute MHV-68 infection.
- To determine if these effector mechanisms exhibit strain-dependent differences in efficacy.
Main Methods:
- Utilized IFN-γ/pfp double knockout (DKO) mice and wild-type (WT) controls.
- Administered IFN-γ blocking antibodies to WT mice.
- Assessed viral titers and mortality rates post-infection.
- Compared infection control in BALB/C and C57BL/6 mouse strains.
Main Results:
- IFN-γ knockout (KO) and DKO mice exhibited higher viral loads and mortality compared to WT mice in BALB/C background.
- Perforin deficiency exacerbated viral titers and mortality in IFN-γ/pfp DKO mice compared to IFN-γ KO mice, indicating a protective role for perforin.
- WT mice treated with IFN-γ blocking antibodies showed increased viral titers.
- IFN-γ KO mice on a C57BL/6 background controlled infection similarly to WT mice, highlighting strain-dependent differences.
Conclusions:
- IFN-γ is crucial for controlling MHV-68 in BALB/C mice, whereas perforin plays a redundant role.
- Significant strain-dependent variations exist in the immune effector mechanisms required for MHV-68 control between C57BL/6 and BALB/C mice.
- Therapeutic strategies for viral reactivation show strain-specific dependencies on perforin (C57BL/6) or IFN-γ (BALB/C).
