Identifying host genetic determinants that regulate dendritic cell activation

识别调节树突状细胞激活的宿主遗传决定因素

基本信息

批准号：
9094679
负责人：
Mehul Shamal Suthar
金额：
$ 21.53万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9094679
关键词：
Address Antiviral Agents Antiviral Response Autoimmunity B-Lymphocytes Bacterial Infections Complex Dendritic Cells Dendritic cell activation Development Embryo Environmental Risk Factor Exhibits Fibroblasts Foundations Gene Expression Genes Genetic Genetic Determinism Genetic Variation Genome HIV Health Hepatitis C virus Human Human Genome Immune Immune response Immunity Immunology In Vitro Inbred Mouse Infection Interferon Type I Interferon-beta Interferons International Kinetics Knowledge Link Malignant Neoplasms Maps Mediating Mental disorders Modeling Molecular Profiling Mus Mycoses Obesity Outcome Pathogenesis Pathway interactions Pattern recognition receptor Pharmaceutical Preparations Population Predisposition Production Quantitative Trait Loci RNA Virus Infections Receptor Signaling Recombinants Resources Risk Factors Severity of illness Signal Pathway Signal Transduction Symptoms System Systems Biology T-Lymphocyte Time Toll-like receptors Transcript Translational Research Vaccination Variant Virus Diseases Virus Replication West Nile virus design genetic approach genetic resource genetic variant genome-wide human disease in vivo influenzavirus insight interdisciplinary approach monocyte novel receptor response tissue tropism trait transcription factor virology

项目摘要

DESCRIPTION (provided by applicant): Host genetic diversity can have a strong impact on susceptibility to viral infection and disease severity. For instance, studies with West Nile virus (WNV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), as well as other viral infections in humans, have identified causal genetic variants that influence viral replication, tissue tropism, disease severity, and infection outcome. However, narrow windows of symptoms, combined with confounding environmental factors, have made it difficult to dissect the genetic mechanisms underlying immunity, pathogenesis and infection outcome. Recent international efforts have developed a novel mouse genetic resource, called the Collaborative Cross (CC), designed to model the complexities of the human genome and support an integrative systems genetics approach to understand complex human diseases (e.g. host response to virus infection). The CC is the only mammalian resource with an infinitely reproducible population comprised of high and uniform genome wide variation. In fact, the CC is being used to study diverse medically-relevant traits, including obesity, psychiatric disorders, cancer, autoimmunity, as well as to identify risk factors of fungal, bacterial, and viral infection. At this time, little is known about how genetic diversity influences innate immune signaling in response to virus infection and vaccination. We seek to address this gap in our knowledge. We hypothesize that host genetic variation impacts innate immune sensing and antiviral responses within dendritic cells (DCs). The RIG-I like receptors (RLRs) are pattern recognition receptors that are essential for inducing type I interferon (IFN), antiviral gene expression and promoting B and T cell immunity in response to WNV and other RNA virus infections. We recently observed that WNV-infected primary mouse embryonic fibroblasts derived from the eight CC founder strains exhibited differences in kinetics and magnitude of IFN-ß induction. Through a preliminary screen to evaluate RIG-I signaling within DCs derived from a set of CC lines, we identified a hyper-responsive (AU8005 17.8 fold increased) and hypo-responsive CC line (OR3032- 9.8 fold decreased) that differentially triggered IFN-ß expression relative to C57BL/6J mice. In support of our findings, a recent analysis within human monocytes and DCs identified causal genetic variants that impact toll-like receptor signaling and the antiviral response to influenza virus infection. To investigate our hypothesis, we will use an interdisciplinary approach involving genetics, immunology, virology, and systems biology to identify genetic variants that regulate RLR signaling and DC innate immune responses. Specifically, we will: 1) investigate the impact of genetic diversity on innate immune sensing; and 2) identify genetic variants that regulate RLR signaling in DCs. These studies will provide a greater insight into host genetics and innate immune signaling and establish a foundation for development of immune-modulatory drugs that can more efficiently activate the innate-adaptive immune interface across a wide range of genetic backgrounds.

描述（适用提供）：宿主遗传多样性对病毒感染和疾病严重程度的敏感性有很大的影响。例如，西尼罗河病毒（WNV），丙型肝炎病毒（HCV），人类免疫缺陷病毒（HIV）以及人类的其他病毒感染的研究已经鉴定出影响病毒复制，组织疾病，疾病的严重性和感染结果的因果遗传变异。然而，狭窄的症状窗户，再加上混杂的环境因素，使得很难剖析免疫学，发病机理和感染结果的遗传机制。最近的国际努力开发了一种新型的小鼠遗传资源，称为协作杂交（CC），旨在对人类基因组的复杂性进行建模，并支持一种综合的系统遗传学方法来了解复杂的人类疾病（例如，宿主对病毒感染的反应）。 CC是唯一具有无限再现种群的哺乳动物资源，由高和均匀的基因组宽变异组成。实际上，CC被用于研究与医学上与医学上有关的特征，包括肥胖，精神疾病，癌症，自身免疫性，以及鉴定真菌，细菌和病毒感染的危险因素。目前，关于遗传多样性如何影响病毒感染和疫苗接种的遗传多样性如何影响先天免疫信号。我们试图根据我们的知识解决这一差距。我们假设宿主遗传变异会影响树突状细胞内的先天免疫传感和抗病毒反应（DCS）。 RIG-I喜欢的受体（RLR）是模式识别受体，对于诱导的I型干扰素（IFN），抗病毒基因表达和促进B和T细胞免疫学对WNV和其他RNA病毒感染而促进B和T细胞免疫学。我们最近观察到，WNV感染的原代小鼠胚胎成纤维细胞源自八个CC创建者菌株暴露于IFN-β诱导的动力学和幅度的差异。通过初步屏幕，可以评估从一组CC系列的DC中评估RIG-I信号传导，我们确定了超响应性（AU8005 17.8倍增加）和低反应性CC线（OR3032-9.8倍）（降低）相对于C57BL/6J小鼠的IFN-β表达差异触发。支持我们的发现，人类单核细胞和DC中的最新分析确定了影响收费类受体信号传导以及对影响病毒感染的抗病毒反应的因果遗传变异。为了研究我们的假设，我们将使用涉及遗传学，免疫学，病毒学和系统生物学的跨学科方法来识别调节RLR信号传导和直流先天免疫调查的遗传变异。具体来说，我们将：1）研究遗传多样性对先天免疫传感的影响； 2）确定调节DC中RLR信号的遗传变异。这些研究将为宿主遗传学和先天免疫信号提供更深入的见解，并为开发免疫调节药物建立基础，这些药物可以更有效地激活各种遗传背景的先天自适应免疫界面。