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。包括我们实验室的工作在内的大量证据支持这样一个概念，即多细胞免疫反应的协调和性质的早期事件对于决定病毒是否被清除或是否建立持久性至关重要。然而，尽管每年约有40,000名感染丙型肝炎病毒的妇女怀孕，但对这种情况下保护性免疫的免疫发病机制或相关因素知之甚少，部分原因是迄今为止，患有慢性丙型肝炎病毒的孕妇一直被排除在免疫研究之外。我们首次提出证据表明，滋养细胞是胎盘的特化细胞，在胚胎着床和与去人格化的母体子宫的相互作用中发挥重要作用，它可以吸收HCV蛋白，并通过产生高水平的III型ifn来响应丙型肝炎病毒产物（称为病原体相关分子模式或PAMP）。这些有趣的结果证实了最近的研究表明，编码干扰素lambda 3的单核苷酸多态性与丙型肝炎病毒的自发恢复有关。此外，我们已经在母胎界面中发现了hcv特异性CD8+ T细胞，我们假设这些细胞在大多数情况下具有防止传播的多种功能属性。我们还将研究蜕膜中的抗原呈递细胞如何在母胎界面内交叉呈递来自滋养细胞和初始CD8+ T细胞的HCV抗原。因此，我们的建议试图从机制上理解支持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.