HEPATITIS C VIRAL INFECTION IN HUMAN PREGNANCY

人类妊娠期丙型肝炎病毒感染

• 批准号: 8535990
• 负责人: HUGO Ramon ROSEN
• 金额: $ 53.19万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535990
• 关键词: Accounting; Affect; Antiviral Agents; Apoptosis; Autologous; Avidity; Beds; Birth; Blood; Blood flow; CD8B1 gene; Cells; Childhood; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Containment; Data; Development; Employee Strikes; Event; Fetal Growth Retardation; Fetus; Genome; HIV; Health; Hepatitis C; Hepatitis C Transmission; Hepatitis C virus; Human; Immune; Immune response; Immunity; Infant; Infection; Interferons; Laboratories; Lead; Liver Failure; Maternal-Fetal Exchange; Mediating; Memory; Modeling; Molecular; Mothers; Natural Immunity; Natural Killer Cells; Nature; Patients; Pattern; Perinatal Exposure; Perinatal mortality demographics; Phenotype; Placenta; Play; Pregnancy; Pregnant Women; Prevalence; RNA Viruses; Recovery; Regulation; Risk; Risk Factors; Role; Signal Transduction; Single Nucleotide Polymorphism; T-Lymphocyte; Termination of pregnancy; Testing; Time; Umbilical Cord Blood; United States; Uterus; Vertical Disease Transmission; Viral; Viral Pathogenesis; Viremia; Virus; Virus Diseases; Woman; Work; adaptive immunity; base; chemokine; cohort; cross reactivity; fetal; genetic association; in vitro Model; in vivo; insight; model design; natural Blastocyst Implantation; novel; particle; pathogen; peripheral blood; prevent; response; transcytosis; transmission process; trophoblast

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.

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。大量证据，包括我们实验室的工作，支持多细胞免疫反应的协调和性质的早期事件在确定病毒是否被清除或是否建立持久性方面至关重要的概念。然而，尽管事实上每年约有40，000例丙型肝炎病毒感染的女性怀孕，但人们对这种情况下丙型肝炎病毒的免疫发病机制知之甚少，部分原因是患有慢性丙型肝炎病毒的孕妇迄今为止一直被排除在免疫研究之外。这是第一次，我们已经确定了HCV特异性的CD8+ T细胞内的母胎界面，我们假设表现出多功能的属性，防止在大多数情况下的传输。而且我们 目前的证据表明，滋养层，胎盘的专门细胞，在胚胎植入和与蜕膜化母体子宫的相互作用中发挥重要作用，可以通过产生高水平的III型IFN（干扰素λ 3）对丙型肝炎病毒产物（称为病原体相关分子模式或PAMP）作出反应。这些有趣的结果证实了最近的研究表明编码干扰素λ 3的单核苷酸多态性与HCV自发恢复的遗传相关性。我们还将描述HCV PAMP如何影响滋养层细胞的凋亡信号和分化。在第三个目标中，建立在强有力的初步数据基础上，T细胞在HCV阳性母亲的胎盘中显着扩增，这些母亲不会将病毒传播给婴儿，我们将描述这些细胞的表型，功能和限制，这些细胞在其他模型中作为抵抗病毒感染的第一道防线。因此，我们的建议旨在机械地理解母胎界面上的不同细胞和信号，这些细胞和信号支持传输与保护，并在胎盘内造成有害影响。虽然重点是HCV感染，但产生的结果将对影响妊娠的其他病毒病原体产生深远的影响。