HEPATITIS C VIRAL INFECTION 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，但在这种情况下，对丙型肝炎病毒的免疫发病机制知之甚少，部分原因是迄今为止，患有慢性丙型肝炎病毒的孕妇被排除在免疫研究之外。我们首次在母胎界面发现了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。此外,我们

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 of HCV in this setting, in part because pregnant women with chronic HCV have hitherto been excluded from studies of immunity. For the first time, 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. Furthermore, we present evidence that trophoblasts, specialized cells of the placenta that play important roles in embryo implantation and interaction with decidualized maternal uterus, can 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 (interferon lambda 3). These intriguing results corroborate the recent studies demonstrating genetic associations with single nucleotide polymorphisms that encode interferon lambda 3 and spontaneous recovery from HCV. We will also characterize how the HCV PAMP affects apoptosis signaling and differentiation of trophoblasts. In the third aim, building on strong preliminary data that ?¿ T cells are significantly expanded within the placentas of HCV-positive mothers who do not transmit virus to their infants, we will characterize the phenotype, function, and restriction of these cells, implicated in other models as a first line of defense against viral infections. Thus, our proposal seeks to mechanistically understand the different cells and signals at the maternal-fetal interface that underpin transmission versus protection and cause detrimental effects within the placenta. Although focused on HCV infection, the results generated will have far-reaching implications for other viral pathogens that affect pregnancy.