Genetic Dissection of arenavirus-induced lethality

沙粒病毒引起的致死率的基因剖析

基本信息

批准号：
9088332
负责人：
ROBERTO G BACCALA
金额：
$ 24.06万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2015-06-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9088332
关键词：
Affect Area Arenaviridae Arenavirus Arenavirus Infections Backcrossings Bioterrorism Blood Platelets Blood Vessels Case Fatality Rates Categories Cessation of life Characteristics Clinical Code Computer Retrieval of Information on Scientific Projects Database DNA Dengue Virus Disease Dissection Edema Endothelial Cells Extravasation Family Gene Mutation Gene Transfer Techniques Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genome Health Immune Immune System Diseases Inbred NZB Mice Individual Infection Interferons Lassa Fever Lassa virus Lymphocytic choriomeningitis virus Mediating Modeling Molecular Mus Mutant Strains Mice Mutate Mutation Old World Arenaviruses Organ failure Pathogenesis Pathology Pathway interactions Pattern Phenotype Polymorphic Microsatellite Marker Population Predisposition RNA Splicing Resistance Ribavirin Role Subgroup Syndrome Technology Testing Therapeutic Intervention Time Tissues Vaccines Variant Vascular Diseases Vascular Permeabilities Viral Viral Hemorrhagic Fevers Virus base genome sequencing hemorrhagic fever virus immunopathology insight interest molecular targeted therapies mortality mutant overexpression pathogen prototype research study response whole genome

项目摘要

DESCRIPTION (provided by applicant): Hemorrhagic fever viruses cause severe clinical manifestations with high case fatality rates and are serious bioterrorism threats. Among them, Lassa virus (LASV) is the second most common cause of hemorrhagic fevers worldwide, infects hundreds of thousands of individuals annually, culminating in ~5,000 to 20,000 deaths per year. There is no approved vaccine and treatment options are limited. The main characteristics of Lassa and other hemorrhagic fevers are endothelial damage, platelet loss and vascular leakage, leading to tissue edema, organ failure and death in severe cases. However, how differences in immune and endothelial cell responses to LASV might affect vascular integrity, and the genetic basis for susceptibility to severe disease, have not been defined. We recently showed that the lymphocytic choriomeningitis virus (LCMV) variant Cl13, considered a model of LASV, causes in NZB mice (but not in B6 mice) severe IFN-dependent vascular leakage, platelet loss, and death, the main characteristics of hemorrhagic fevers. In additional studies we showed that F1 crosses of NZB and B6 are also susceptible, while F1xB6 backcrosses showed 54% mortality, a pattern compatible with Mendelian dominant inheritance of susceptibility. This proposal will 1) use DNA from affected and non-affected backcrosses to identify for the first time a gene that controls susceptibility to arenavirus-induced lethality, and 2) confirm the relevance of the identified gene by imposing this mutation in non-susceptible B6 mice. The identified gene might encode a molecule previously unrecognized as being a contributor to virus-induced immune and vascular dysfunctions. Thus, the proposed study holds the potential of revealing new mechanistic insights, genetic basis, and molecular targets of therapeutic intervention for Lassa and other viral HF syndromes.

描述（由申请人提供）：出血热病毒可引起严重的临床表现和高病死率，是严重的生物恐怖主义威胁，其中拉沙病毒（LASV）是全球出血热的第二常见原因，每年感染数十万人，最多感染约 5,000 至 5,000 人。每年有 20,000 人死亡。没有批准的疫苗，治疗方案也有限。拉沙热和其他出血热的主要特征是内皮损伤。血小板丢失和血管渗漏，导致组织水肿、器官衰竭，严重时甚至死亡。然而，免疫细胞和内皮细胞对 LASV 反应的差异如何影响血管完整性以及易患严重疾病的遗传基础尚未明确。我们最近发现，淋巴细胞性脉络膜脑膜炎病毒 (LCMV) 变种 Cl13（被认为是 LASV 模型）会导致 NZB 小鼠（但不会在 B6 小鼠中）严重的 IFN 依赖性血管病渗漏、血小板丢失和死亡是出血热的主要特征。在其他研究中，我们表明 NZB 和 B6 的 F1 杂交也易感，而 F1xB6 回交显示出 54% 的死亡率，这一模式与孟德尔显性遗传的易感性相一致。该提案将 1) 使用来自受影响和未受影响回交的 DNA 来首次识别控制沙粒病毒诱导致死率易感性的基因，以及2）通过在非易感性 B6 小鼠中施加这种突变来确认所识别基因的相关性。所识别的基因可能编码一种以前未被识别为病毒引起的免疫和血管功能障碍的分子。因此，拟议的研究具有潜力。揭示拉沙和其他病毒性心力衰竭综合征治疗干预的新机制见解、遗传基础和分子靶点。