INNATE AND ADAPTIVE IMMUNITY TO HCV IN HUMAN PREGNANCY

描述(申请人提供)：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，总体流行率为~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，支持这样的概念，即多细胞免疫反应的协调和性质中的早期事件对于确定病毒是否被清除或持久性是否建立至关重要。然而，尽管每年在感染丙型肝炎病毒的妇女中大约有40,000例怀孕，但人们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，部分原因是患有慢性丙型肝炎病毒的孕妇迄今被排除在免疫研究之外。我们首次提出证据表明，滋养层细胞，胎盘的专门细胞，在胚胎植入和与蜕膜形成的母体子宫相互作用中发挥重要作用，可以结合丙型肝炎病毒蛋白，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)。这些耐人寻味的结果证实了最近的研究表明，编码干扰素lambda 3的单核苷酸多态与丙型肝炎病毒自发恢复之间存在遗传关联。此外，我们已经在母胎界面中发现了丙型肝炎病毒特异的CD8+T细胞，我们推测这些细胞具有多种功能属性，在大多数情况下可以防止传播。我们还将研究蜕膜中的抗原提呈细胞如何交叉提呈滋养层细胞和母体胎儿界面内的CD8+T细胞。因此，我们的建议试图机械地理解支撑丙型肝炎病毒传播和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.