Illumination of Murine Gammaherpesvirus-68 Cycle Reveals a Sexual Transmission Route from Females to Males in Laboratory Mice

Transmission is a matter of life or death for pathogen lineages and can therefore be considered as the main motor of their evolution. Gammaherpesviruses are archetypal pathogenic persistent viruses which have evolved to be transmitted in presence of specific immune response. Identifying their mode of transmission and their mechanisms of immune evasion is therefore essential to develop prophylactic and therapeutic strategies against these infections. As the known human gammaherpesviruses, Epstein-Barr virus and Kaposi's Sarcoma-associated Herpesvirus are host-specific and lack a convenient in vivo infection model; related animal gammaherpesviruses, such as murine gammaherpesvirus-68 (MHV-68), are commonly used as general models of gammaherpesvirus infections in vivo. To date, it has however never been possible to monitor viral excretion or virus transmission of MHV-68 in laboratory mice population. In this study, we have used MHV-68 associated with global luciferase imaging to investigate potential excretion sites of this virus in laboratory mice. This allowed us to identify a genital excretion site of MHV-68 following intranasal infection and latency establishment in female mice. This excretion occurred at the external border of the vagina and was dependent on the presence of estrogens. However, MHV-68 vaginal excretion was not associated with vertical transmission to the litter or with horizontal transmission to female mice. In contrast, we observed efficient virus transmission to naïve males after sexual contact. In vivo imaging allowed us to show that MHV-68 firstly replicated in penis epithelium and corpus cavernosum before spreading to draining lymph nodes and spleen. All together, those results revealed the first experimental transmission model for MHV-68 in laboratory mice. In the future, this model could help us to better understand the biology of gammaherpesviruses and could also allow the development of strategies that could prevent the spread of these viruses in natural populations.

传播对于病原体谱系而言是关乎生死的关键环节，因此可被视为其演化的核心驱动力。γ疱疹病毒（Gammaherpesviruses）是典型的致病性持续性病毒，其演化出了在特异性免疫应答存在的情况下仍可实现传播的特性。因此，明确其传播模式与免疫逃逸机制，对于开发针对此类感染的预防与治疗策略至关重要。目前已知的人类γ疱疹病毒包括爱泼斯坦-巴尔病毒（Epstein-Barr virus）与卡波西肉瘤相关疱疹病毒（Kaposi's Sarcoma-associated Herpesvirus），二者均为宿主特异性病毒，且缺乏便捷的体内感染模型；相关的动物γ疱疹病毒（如鼠γ疱疹病毒68（murine gammaherpesvirus-68, MHV-68））则常被用作γ疱疹病毒体内感染研究的通用模型。然而迄今为止，学界始终无法在实验小鼠种群中监测MHV-68的病毒排泄与传播情况。本研究中，我们借助搭载全视野荧光素酶成像（luciferase imaging）技术的MHV-68，对实验小鼠体内该病毒的潜在排泄位点展开了探究。该方法帮助我们确认：雌性小鼠经鼻内感染并建立潜伏感染后，MHV-68存在一处生殖道排泄位点。该排泄过程发生于阴道外边缘，且依赖雌激素的存在。但MHV-68的阴道排泄并未与垂直传播至幼崽、或水平传播至其他雌性小鼠相关联。与之相反，我们观察到该病毒可通过性接触高效传播至未感染的雄性小鼠。体内成像技术证实，MHV-68首先会在雄性小鼠的阴茎上皮与海绵体内复制，随后扩散至引流淋巴结与脾脏。综上，本研究结果首次构建了实验小鼠体内MHV-68的实验性传播模型。未来，该模型将有助于我们更深入地解析γ疱疹病毒的生物学特性，同时也可为开发阻断此类病毒在自然种群中传播的策略提供支撑。