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

定义寄生虫驱动的对 γ-疱疹病毒潜伏期影响的机制

基本信息

批准号：
10658591
负责人：
Tiffany Anne Reese
金额：
$ 48.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2028-01-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY The goal of this grant is to understand how bystander infections with intestinal parasites alter chronic infection with γ-herpesviruses. This is important because herpesviruses infect virtually all people and approximately a quarter of the world’s population is simultaneously infected with a parasite. Herpesvirus infections are chronic, but these viruses do not persistently replicate in a healthy host. Instead, they establish a quiescent infection, termed latency. We discovered previously that co-infection with an intestinal helminth parasite after infection with γ-herpesvirus led to increased virus reactivation from latency. We detailed a mechanism whereby reactivation of the virus depended on sensing host cytokines produced in response to the parasite. A remaining question is whether the timing of the dual infections is important. In this grant we propose to address this question by changing the order of virus-parasite co- infection to determine whether reactivation of the virus is increased by parasite infection when the parasite infection occurs before the γ-herpesvirus infection. We have data to indicate that prior infection with an intestinal parasite increases γ-herpesvirus reactivation, but that the mechanism is different than what we discovered previously when parasite infection occurs after the herpesvirus infection. We find that parasite infected animals have increased resident peritoneal macrophages. We also find that when retinoic acid, which is required for maintenance of resident peritoneal macrophages, is depleted in mice, parasite infection no longer increases virus reactivation. Our hypothesis is that parasite infection, in a retinoic acid dependent manner, alters the tissue composition of resident macrophages. This promotes retention of a population of infected macrophages with enhanced γ-herpesvirus reactivation. In this proposal, we aim to examine the role of resident macrophages and retinoic acid in parasite-induced herpesvirus reactivation. These studies will deliver insight into the mechanisms that drive herpesvirus reactivation during co-infection and will increase our understanding of parasite modulation of tissue resident macrophages. Harnessing the power of mouse model pathogens, these studies will advance our understanding of pathogen co-infection.

项目摘要这项资助的目标是了解旁观者感染肠道寄生虫如何改变慢性 γ-疱疹病毒感染。这一点很重要，因为疱疹病毒几乎感染所有人，世界上大约四分之一的人口同时感染了寄生虫。疱疹病毒感染是慢性的，但这些病毒不会在健康宿主中持续复制。而是建立一个静止的感染，称为潜伏期。我们之前发现，肠道蠕虫寄生虫感染γ-疱疹病毒后，延迟。我们详细说明了一种机制，即病毒的重新激活依赖于感知宿主细胞因子是寄生虫引起的剩下的问题是双重感染的时间是否重要.在这项研究中，我们建议通过改变病毒-寄生虫共- 感染，以确定是否重新激活的病毒是增加寄生虫感染时，寄生虫感染发生在γ-疱疹病毒感染之前。我们有数据表明先前的感染与肠道寄生虫一起增加γ-疱疹病毒的再活化，但其机制与我们之前发现的是疱疹病毒感染后发生寄生虫感染。我们发现感染寄生虫的动物体内的腹腔巨噬细胞增多我们还发现，当维持驻留的腹膜巨噬细胞所需的视黄酸，在小鼠中被耗尽，寄生虫感染不再增加病毒再活化。我们的假设是，寄生虫感染，在一个视黄酸依赖的方式，改变驻留巨噬细胞的组织组成。这促进保留受感染的巨噬细胞群体，增强γ-疱疹病毒再活化。在这建议，我们的目的是检查居民巨噬细胞和维甲酸在寄生虫诱导的疱疹病毒再激活这些研究将深入了解疱疹病毒的驱动机制，在共同感染期间重新激活，并将增加我们对组织寄生虫调节的理解常驻巨噬细胞利用小鼠模型病原体的力量，这些研究将推动我们的研究。了解病原体共感染。