Defining Mechanisms for Parasite-Driven Effects on Gamma-Herpesvirus Latency

项目总结 这笔赠款的目标是了解旁观者感染如何改变γ的慢性感染- 疱疹病毒。这一点很重要，因为疱疹病毒几乎感染所有人，并终生存在。 主人的名字。这意味着接触旁观者可能会改变疱疹病毒的感染。 感染。即使疱疹病毒感染是慢性的，这些病毒也不会持续地在 一个健康的主人。相反，他们建立了一种静止的感染，称为潜伏期。这种潜伏的感染 疱疹病毒受到宿主免疫系统的严密控制，而免疫系统的变化 调节疱疹病毒的感染状态，导致病毒从潜伏期重新激活。我们发现 与肠道蠕虫寄生虫混合感染可诱导γ疱疹病毒重新激活。我们确定了 蠕虫感染过程中产生的宿主细胞因子、白介素4和白介素13对 γ-疱疹病毒重新激活。我们还发现了一种由IL-4/IL-13直接调控的病毒启动子 发信号。然而，蠕虫介导的疱疹病毒在体内重新激活的机制仍然是 不完全理解。我们将利用我们独特的疱疹病毒蠕虫实验系统 在小鼠身上探索这些共同感染的机制。我们假设寄生虫感染 γ-疱疹病毒感染的多种影响取决于双重感染的时间或顺序 感染。我们建议进一步详细说明疱疹病毒对IL-4/IL-13信号转导的要求。 蠕虫合并感染，并确定感染时机对观察到的表型的贡献。 这项建议将增加我们对宿主调节疱疹病毒潜伏期和作用的理解 旁观者感染在疱疹病毒感染中起作用。这对于理解这些病毒是如何 驱动病理并改变宿主免疫系统。

PROJECT SUMMARY The goal of this grant is to understand how bystander infections alter chronic infection with γ- herpesviruses. This is important because herpesviruses infect virtually all people and persist for the life of the host. This means that herpesvirus infection is potentially altered by exposure to bystander infections. Even though herpesvirus infections are chronic, these viruses do not persistently replicate in a healthy host. Instead, they establish a quiescent infection, termed latency. This latent infection with herpesviruses is tightly controlled by the host immune system, and changes in the immune system modulate the state of herpesvirus infection, leading to virus reactivation from latency. We found that co-infection with an intestinal helminth parasite induced γ-herpesvirus reactivation. We identified the host cytokines, interleukin (IL)-4 and IL-13 that are produced during helminth infection to be critical for γ-herpesvirus reactivation. We also identified a viral promoter that is directly regulated by IL-4/IL-13 signaling. However, the mechanisms for helminth-mediated herpesvirus reactivation in vivo are still incompletely understood. We will leverage our unique experimental systems of herpesvirus-helminth co-infection to explore these mechanisms in the mouse. We hypothesize that parasite infection has multiple effects of γ-herpesvirus infection that are dependent on the timing or order of the dual infections. We propose to further detail the requirements for IL-4/IL-13 signaling in herpesvirus- helminth co-infection, and to define the contribution of infection timing to the phenotypes observed. This proposal will increase our understanding of host regulation of herpesvirus latency and the role bystander infections play in herpesvirus infection. This is critical to understanding how these viruses drive pathologies and alter the host immune system.