INNATE AND ADAPTIVE IMMUNITY TO HCV IN HUMAN PREGNANCY

摘要 丙型肝炎病毒（HCV）是美国最常见的血液传播感染，总体而言， 患病率约为2%，全世界估计有2亿慢性感染者。了大量的 证据，包括我们实验室的工作，支持这一概念，即早期事件的协调和 多细胞免疫应答的性质在确定病毒是否被清除或是否 持久性已经建立。然而，尽管每年大约有40 000例怀孕， 在HCV感染的妇女中，对HCV感染的免疫发病机制或保护性免疫的相关性知之甚少， 这种情况下，部分原因是孕妇与慢性丙型肝炎病毒迄今已被排除在研究 免疫力这是我们第一次提出证据，证明滋养层，胎盘的专门细胞， 在胚胎着床和与蜕膜化母体子宫的相互作用中起重要作用，可摄取HCV 蛋白质以及对丙型肝炎病毒产物（称为病原体相关分子）的反应 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的单核苷酸多态性与遗传相关 λ 3和从HCV自发恢复。此外，我们还鉴定了HCV特异性CD 8 + T细胞， 在我们假设的母胎界面中， 在大多数情况下，传播。我们还将研究蜕膜中的抗原呈递细胞如何交叉- 从滋养层呈递HCV抗原，并在母胎界面内引发CD 8 + T细胞。因此，在本发明中， 我们的建议旨在从机制上理解支持HCV的不同细胞和信号 传输与保护。

ABSTRACT 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.