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Evidence that NK cells and interferon are required for genetic resistance to lethal infection with ectromelia virus
R O Jacoby1, P N Bhatt, D G Brownstein
1Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut.
Abstract:
C 57 BL/6 mice developed resistance to lethal intravenous challenge with virulent (Moscow strain) ectromelia virus between 2 and 3 weeks of age. The fraction of C57 BL/6 mice in which virus was detected in spleen was significantly lower than for DBA/2 mice by day 3. Thereafter, C 57 BL/6 mice had significantly reduced virus titers in spleen compared with those of DBA/2 mice. Resistance was abrogated by treatment with anti-asialo GM1 gammaglobulin, which blocks NK cell activity, or with anti-interferon (IFN) alpha, beta. C 57 BL/6 mice carrying the bg/bg mutation, associated with a deficiency of NK cells, were highly susceptible to lethal infection as were athymic mice derived from a resistant genetic background. Virus titers in spleens of C 57 BL/6 mice treated with anti-asialo GM1 or anti-IFN alpha, beta were significantly higher 4 days after virus challenge than were titers in C 57 BL/6 mice treated with normal rabbit serum. The results strongly suggest that genetic resistance to lethal ectromelia virus infection requires non-specific host defenses such as NK cells and IFN alpha, beta that are activated during the first 3 to 4 days of infection.
Insights
Genetic resistance to lethal ectromelia virus infection in mice relies on innate immune defenses. Natural killer (NK) cells and interferon (IFN) alpha, beta are crucial for early antiviral responses.
Area of Science:
- Immunology
- Virology
- Genetics
Background:
- C57 BL/6 mice exhibit age-dependent resistance to ectromelia virus.
- DBA/2 mice are more susceptible to ectromelia virus infection.
Purpose of the Study:
- To investigate the role of innate immune mechanisms in genetic resistance to ectromelia virus.
- To elucidate the contribution of Natural Killer (NK) cells and Interferon (IFN) to ectromelia virus resistance.
Main Methods:
- Ectromelia virus challenge in C57 BL/6 and DBA/2 mice.
- Treatment with anti-asialo GM1 gammaglobulin to block NK cell activity.
- Treatment with anti-interferon (IFN) alpha, beta.
- Assessment of virus titers in spleen and susceptibility in genetically modified mice (bg/bg and athymic).
Main Results:
- C57 BL/6 mice showed significantly lower viral detection in spleen by day 3 and reduced viral titers compared to DBA/2 mice.
- Resistance was abolished by blocking NK cell activity or IFN alpha, beta.
- Mice deficient in NK cells (bg/bg) or athymic mice were highly susceptible.
- Blocking NK cells or IFN alpha, beta led to significantly higher virus titers in C57 BL/6 mice.
Conclusions:
- Genetic resistance to lethal ectromelia virus infection is mediated by non-specific host defenses.
- Natural killer (NK) cells and interferon (IFN) alpha, beta are critical components of the early antiviral response against ectromelia virus.