INNATE AND ADAPTIVE IMMUNITY TO HCV IN HUMAN PREGNANCY

描述（由申请人提供）：丙型肝炎病毒（HCV）是美国最常见的血源性感染，总体患病率约为2%，全球估计有2亿慢性感染者。大量证据，包括我们实验室的工作，支持多细胞免疫反应的协调和性质的早期事件在确定病毒是否被清除或是否建立持久性方面至关重要的概念。然而，尽管事实上，每年约有40，000例妊娠发生在HCV感染的女性中，但对这种情况下的免疫发病机制或保护性免疫的相关性知之甚少，部分原因是慢性HCV孕妇迄今为止一直被排除在免疫研究之外。这是第一次，我们提出的证据表明，滋养层细胞，胎盘的专门细胞，在胚胎植入和与蜕膜化的母体子宫的相互作用中发挥重要作用，可以采取HCV蛋白，以及响应丙型肝炎病毒的产品（称为病原体相关的分子模式或PAMP）通过产生高水平的III型IFN。这些有趣的结果证实了最近的研究表明编码干扰素λ 3的单核苷酸多态性与HCV自发恢复的遗传相关性。此外，我们已经确定了母胎界面内的HCV特异性CD8+ T细胞，我们假设它们表现出在大多数情况下阻止传播的多功能属性。我们还将研究蜕膜中的抗原呈递细胞如何交叉呈递来自滋养层的HCV抗原和母胎界面内的初始CD8+ T细胞。因此，我们的建议旨在从机制上理解支持HCV传播与保护的不同细胞和信号。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is the most common blood-borne infection in the United States, with an overall prevalence of ~2%, and an estimated 200 million chronically infected people worldwide. A substantial body of evidence, including work from our laboratory, supports the concept that early events in the coordination and nature of multi-cellular immune responses are critical in determining whether the virus is cleared or whether persistence is established. However, despite the fact that approximately 40,000 pregnancies occur each year in HCV-infected women, little is known about the immunopathogenesis or correlates of protective immunity in this setting, in part because pregnant women with chronic HCV have hitherto been excluded from studies of immunity. For the first time, we present evidence that trophoblasts, specialized cells of the placenta that play important roles in embryo implantation and interaction with decidualized maternal uterus, can take up HCV proteins as well as respond to a viral product of hepatitis C (known as a pathogen-associated molecular pattern or PAMP) by producing high levels of Type III IFNs. These intriguing results corroborate the recent studies demonstrating genetic associations with single nucleotide polymorphisms that encode interferon lambda 3 and spontaneous recovery from HCV. Furthermore, we have identified HCV-specific CD8+ T cells within the maternal-fetal interface that we hypothesize demonstrate versatile functional attributes that prevent transmission in the majority of cases. We will also study how antigen-presenting cells in the decidua cross- present HCV antigens from trophoblasts and prime CD8+ T cells within the maternal fetal interface. Thus, our proposal seeks to mechanistically understand the different cells and signals that underpin HCV transmission versus protection.