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）：出血热病毒引起严重的临床表现，病例死亡率很高，并且是严重的生物恐怖威胁。其中，LASSA病毒（LASV）是全球出血性发烧的第二大最常见原因，每年被感染数十万个人，每年约有5,000至20,000人死亡。没有批准的疫苗，治疗方案有限。 LASSA和其他出血狂的主要特征是内皮损伤，血小板损失和血管泄漏，导致严重病例的组织水肿，器官衰竭和死亡。但是，尚未确定免疫和内皮细胞对LASV的反应的差异可能影响血管完整性，以及对严重疾病的易感性的遗传基础。我们最近表明，淋巴细胞性欺骗病毒病毒（LCMV）变体CL13被认为是LASV模型，是NZB小鼠（但在B6小鼠中）的原因（但在B6小鼠中）严重的IFN依赖性IFN依赖性血管泄漏，血小板丢失和死亡，死亡的主要特征，是出血生气的主要特征。在其他研究中，我们表明NZB和B6的F1杂交也易感，而F1XB6反向交叉显示54％的死亡率，这是一种与Mendelian占主导地位的易感性遗传兼容的模式。该提案将1）使用受影响和未受影响的反向交叉的DNA首次鉴定出一种控制竞技表现诱导的致死性易感性的基因，以及2）通过在非抑制的B6小鼠中施加这种突变来确认已识别基因的相关性。鉴定的基因可能编码以前未被认为是导致病毒诱导的免疫和血管功能障碍的分子。这是拟议的研究的潜力，可以揭示针对LASSA和其他病毒HF综合征的治疗干预的新机械见解，遗传基础和分子靶标。