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

摘要 伽马疱疹病毒可导致95%的成年人感染，并与多种癌症有关，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 潜伏感染和旁观者B细胞进入生发中心反应，最终实现终生潜伏期 记忆B细胞。重要的是，生发中心的反应是高度诱变的，被认为是目标。 病毒转化的可能性。伽马疱疹病毒侵占B细胞分化的机制包括 生发中心的反应，很大程度上是未知的。这一建议是基于我们的发现，IL-17A 选择性地促进伽马疱疹病毒驱动的生发中心反应和病毒重新激活，两个 与病毒淋巴增生症风险增加相关的过程。IL-17A是由和诱导的 有助于清除细菌和真菌病原体，我们的研究揭示了一种意想不到的 这种细胞因子的前驱作用。拟议的研究验证了这样的假设，即自然诱导的IL-17A是通过 细菌病原体被伽马疱疹病毒取代，以促进生发中心反应和 病毒重新激活。拟议的研究将确定系统性或解剖学上的 限制性细菌感染对伽马疱疹病毒驱动的生发中心反应和病毒再激活的影响 并利用宿主和细菌遗传学来确定IL-17A在这一过程中的作用。圆满完成 拟议的研究将首次确定由普通细菌诱导的自然IL-17A的影响 病原体与病毒淋巴增生症相关的关键致病过程，并将提供洞察力 针对病毒驱动的淋巴瘤易感性的新方法。

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.