Gender Influences Herpes Simplex Virus Type 1 Infection in Normal and Gamma Interferon-Mutant Mice

Gender influences the incidence and severity of some bacterial and viral infections and autoimmune diseases in animal models and humans. To determine a gender-based difference, comparisons were made between male and female mice inoculated with herpes simplex virus type 1 (HSV-1) by the corneal route. Mortality was higher in the male mice of the three strains tested: 129/Sv//Ev wild type, gamma interferon (IFN-γ) knockout (GKO), and IFN-γ receptor knockout (RGKO). Similarly, in vivo HSV-1 reactivation occurred more commonly in male mice, but the male-female difference in reactivation was restricted to the two knockout strains and was not seen in the 129/Sv//Ev control. Comparison among male mice of the three strains showed a higher mortality of the RGKO mice and a higher reactivation rate of the GKO and RGKO mice than of the 129/Sv//Ev males. In contrast, female RGKO and GKO mice did not differ from female 129/Sv//Ev controls in either mortality or reactivation. HSV-1 periocular and eyelid disease was also more severe in male and dihydrotestosterone (DHT)-treated female mice than in control female mice. These results show a consistent gender difference in HSV-1 infection, with a worse outcome in male mice. In addition, the results comparing GKO and RGKO mice to controls show differences only in male mice, suggesting that some effects of IFN-γ, a key immunoregulatory molecule, are gender specific.

性别会对动物模型与人类中部分细菌、病毒感染及自身免疫疾病的发病率与严重程度产生影响。为明确性别相关差异，本研究对经角膜途径接种1型单纯疱疹病毒（herpes simplex virus type 1, HSV-1）的雌雄小鼠开展了对比实验。在所测试的三个小鼠品系中，雄性小鼠的死亡率均更高，这三个品系分别为129/Sv//Ev野生型、γ干扰素（gamma interferon, IFN-γ）敲除（GKO）小鼠以及IFN-γ受体敲除（RGKO）小鼠。类似地，雄性小鼠体内的HSV-1再激活现象更为普遍，但该再激活的雌雄差异仅见于两个敲除品系，在129/Sv//Ev野生型对照组中未观察到此差异。对三个品系的雄性小鼠进行横向比较后发现，RGKO小鼠的死亡率高于129/Sv//Ev雄性小鼠，而GKO与RGKO小鼠的再激活率也均高于129/Sv//Ev雄性小鼠。与之相反，RGKO与GKO雌性小鼠在死亡率与再激活率方面均与129/Sv//Ev雌性对照组小鼠无显著差异。雄性小鼠以及经双氢睾酮（dihydrotestosterone, DHT）处理的雌性小鼠的HSV-1眼周及眼睑病变也较对照组雌性小鼠更为严重。上述结果证实了HSV-1感染中存在稳定的性别差异，雄性小鼠的感染预后更差。此外，将GKO与RGKO小鼠与对照组进行对比的结果显示，此类差异仅存在于雄性小鼠中，这表明关键免疫调节分子γ干扰素的部分功能具有性别特异性。