Gammaherpesvirus and IL-17: using host antibacterial defense to benefit chronic virus infection

摘要 γ疱疹病毒在>95%的成人中建立感染，并与多种癌症相关，包括 B细胞淋巴瘤这些病毒通过感染幼稚的B细胞并驱动细胞进入而篡夺B细胞分化。 潜伏感染和旁观者B细胞进入生殖中心反应，最终实现终身潜伏， 记忆B细胞。重要的是，生发中心反应是高度致突变的，被认为是靶点。 病毒的转化。γ疱疹病毒篡夺B细胞分化的机制，包括 老年痴呆症中心的反应，在很大程度上是未知的。这个建议是基于我们发现IL-17 A 选择性地促进γ疱疹病毒驱动的生发中心反应和病毒再活化， 与病毒性淋巴瘤发生风险增加相关的过程。IL-17 A是由 有助于清除细菌和真菌病原体，我们的研究揭示了一个意想不到的 这种细胞因子的前病毒作用。所提出的研究检验了IL-17 A的自然诱导是由IL-17 A的分泌引起的这一假设。 细菌病原体被γ-疱疹病毒取代以促进生发中心反应， 病毒再激活拟议的研究将确定系统性或解剖学上 限制性细菌感染影响γ疱疹病毒驱动的生发中心反应和病毒再激活 并使用宿主和细菌遗传学来确定IL-17 A在这一过程中的作用。成功完成 拟议的研究将首次确定普通细菌对天然IL-17 A诱导的影响， 病原体的关键致病过程与病毒性淋巴瘤的发生，并将提供深入了解 新的方法来靶向对病毒驱动的淋巴瘤的易感性。

Abstract Gammaherpesviruses establish infection in >95% of adults and are associated with multiple cancers, including B cell lymphomas. These viruses usurp B cell differentiation by infecting naïve B cells and driving entry of latently infected and bystander B cells into a germinal center response to ultimately achieve life-long latency in memory B cells. Importantly, the germinal center response is highly mutagenic and is thought to be the target of viral transformation. The mechanisms by which gammaherpesviruses usurp B cell differentiation, including germinal center response, are largely unknown. This proposal is based on our discovery that IL-17A selectively promotes the gammaherpesvirus-driven germinal center response and viral reactivation, two processes that are associated with increased risk of viral lymphomagenesis. IL-17A is induced by and contributes to the clearance of bacterial and fungal pathogens, with our studies revealing an unexpected proviral role of this cytokine. The proposed studies test the hypothesis that natural induction of IL-17A by bacterial pathogens is usurped by gammaherpesviruses to promote germinal center response and viral reactivation. The proposed studies will determine the extent to which a systemic or anatomically restricted bacterial infection impacts gammaherpesvirus-driven germinal center response and viral reactivation and use host and bacterial genetics to define the role of IL-17A in this process. Successful completion of the proposed studies will for the first time define the impact of natural IL-17A induction by common bacterial pathogens on the key pathogenic processes associated with viral lymphomagenesis and will provide insight into novel approaches to target susceptibility to virus-driven lymphomas.