INNATE AND ADAPTIVE IMMUNITY TO HCV IN HUMAN PREGNANCY

摘要 丙型肝炎病毒(丙型肝炎病毒)是美国最常见的血液传播感染，总体上 患病率约为2%，全球估计有2亿慢性感染者。一大堆的 证据，包括我们实验室的工作，支持这一概念，早期事件在协调和 多细胞免疫反应的性质是决定病毒是否被清除或是否被清除的关键 坚持不懈是建立起来的。然而，尽管每年约有4万例怀孕 在感染丙型肝炎病毒的妇女中，对免疫发病机制或保护性免疫的相关性知之甚少。 这一背景，部分是因为到目前为止，患有慢性丙型肝炎的孕妇被排除在 豁免权。第一次，我们提出证据，滋养层细胞，胎盘的特化细胞 在胚胎植入中的重要作用以及与蜕膜化母体子宫的相互作用，可感染丙型肝炎病毒 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。这些耐人寻味的结果证实了最近的 编码干扰素的单核苷酸多态与遗传相关性的研究 Lambda 3和丙型肝炎病毒自然恢复。此外，我们还鉴定了丙型肝炎病毒特异性CD8+T细胞 在我们假设的母胎界面内，展示了多种功能属性，防止 在大多数情况下传播。我们还将研究蜕膜中的抗原提呈细胞如何交叉 目前的丙型肝炎病毒抗原来自滋养层细胞和母体胎儿界面内的初始CD8+T细胞。因此， 我们的计划试图机械地理解支撑丙型肝炎病毒的不同细胞和信号 传播对抗保护。

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.