INNATE AND ADAPTIVE IMMUNITY TO HCV IN HUMAN PREGNANCY

人类妊娠期对 HCV 的先天性和适应性免疫

基本信息

批准号：
8654226
负责人：
MARGARET G PETROFF
金额：
$ 33.6万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-07 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8654226
关键词：
Accounting Antigen-Presenting Cells Antiviral Agents Antiviral Response Apoptosis Avidity Beds Birth Blood Blood flow CD28 gene CD8B1 gene Cells Child Childhood Chronic Chronic Hepatitis C Clinical Collaborations Containment Cross Presentation Decidua Dendritic Cells Development Employee Strikes Event Evolution Fetal Growth Retardation Fetus Flow Cytometry Genes Genome HIV Hepatitis C Hepatitis C Transmission Hepatitis C virus Human Immune Immune response Immunity Immunology Immunotherapeutic agent Individual Infection Interferons Laboratories Maternal-Fetal Exchange Mediating Memory Modeling Molecular Mothers National Institute of Child Health and Human Development Natural Immunity Nature Patients Pattern Pattern recognition receptor Peptides Perinatal Exposure Perinatal mortality demographics Phenotype Placenta Play Population Pregnancy Pregnant Women Prevalence Property RNA Viruses Recovery Risk Role SELL gene Signal Transduction Single Nucleotide Polymorphism Small Interfering RNA Stem cells T-Lymphocyte T-Lymphocyte Subsets Termination of pregnancy Testing Time Tretinoin Umbilical Cord Blood United States Uterus Variant Vertical Disease Transmission Viral Viral Antigens Viral Proteins Viremia Virus Virus Diseases Woman Work adaptive immunity cohort cross reactivity cytotoxic fetal medicine genetic association insight natural Blastocyst Implantation novel particle pathogen peripheral blood pressure prevent public health relevance response self-renewal transmission process trophoblast viral RNA

项目摘要

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.

抽象的丙型肝炎病毒 (HCV) 是美国最常见的血源性感染，总体而言患病率约为 2%，全球估计有 2 亿慢性感染者。一个实质性的机构包括我们实验室的工作在内的证据支持这一概念，即早期事件在协调和多细胞免疫反应的性质对于确定病毒是否被清除或是否被清除至关重要持久性已建立。然而，尽管每年约有 40,000 例怀孕发生在 HCV 感染女性中，人们对免疫发病机制或保护性免疫的相关性知之甚少。这种情况的部分原因是迄今为止，患有慢性丙型肝炎的孕妇被排除在研究之外免疫。我们首次提出证据表明滋养层细胞（胎盘的特殊细胞）发挥作用在胚胎着床和与蜕膜化母体子宫相互作用中发挥重要作用，可以吸收丙型肝炎病毒蛋白质以及对丙型肝炎病毒产物（称为病原体相关分子）做出反应模式或 PAMP）通过产生高水平的 III 型干扰素。这些有趣的结果证实了最近的研究证明与编码干扰素的单核苷酸多态性存在遗传关联 lambda 3 和 HCV 自发恢复。此外，我们还鉴定出了 HCV 特异性 CD8+ T 细胞在我们假设的母胎界面中，它表现出多种功能属性，可以防止大多数情况下都会传播。我们还将研究蜕膜中的抗原呈递细胞如何交叉呈递来自母体胎儿界面内的滋养层和初级 CD8+ T 细胞的 HCV 抗原。因此，我们的提案旨在从机制上理解支持 HCV 的不同细胞和信号传输与保护。