IDENTIFICATION OF HOST GENETIC DETERMINANT CAUSING SEVERE INFLUENZA PATHOGENESIS

导致严重流感发病的宿主遗传决定因素的鉴定

• 批准号: 8800540
• 负责人: Adrianus CM Boon
• 金额: $ 24.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-05 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800540
• 关键词: A/J Mouse; Affect; Africa; Animals; Antiviral Agents; Asthma; Biological; Biology; C57BL/6 Mouse; Candidate Disease Gene; Cells; Cessation of life; Chromosomes; Chromosomes, Human, Pair 4; Congenic Mice; Data; Diabetes Mellitus; Disease; Elderly; Epidemic; Epidemiology; Far East; Future; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genetic screening method; Health; Human; Immune response; Immunologics; In Vitro; Inbred Strains Mice; Individual; Infection; Inflammation; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza B Virus; Integration Host Factors; Kinetics; Lung; Measures; Mouse Strains; Mus; Mutation; Pathogenesis; Pathology; Persons; Positioning Attribute; Predisposition; Process; Production; Property; Public Health; RNA Interference; Reporting; Resistance; Respiratory System; Respiratory tract structure; Role; Sendai virus; Severities; Severity of illness; Single Nucleotide Polymorphism; Testing; Variant; Viral; Viral Load result; Viral Pathogenesis; Viral load measurement; Virus Diseases; Virus Replication; West Nile virus; base; burden of illness; consomic; cytokine; design; experience; gene function; influenzavirus; insight; microbial; mortality; novel; pandemic disease; pandemic influenza; pathogen; receptor expression; research study; sialic acid receptor; virus pathogenesis

DESCRIPTION (provided by applicant): Highly pathogenic H5N1 influenza virus continues to circulate in South-East Asia and Africa. Since 2003, over 550 human cases of H5 N1 infections have been reported and approximately 50% of those cases have died. Although the exact number of H5N1 infected persons is unknown, the severity of the resulting disease in those that have been identified is driven by a combination of viral and host factors. Evidence shows that host genetic polymorphisms are involved in H5N1 pathogenesis and identifying them, and the affected host genes, will reveal important biological properties of H5N1 virus infections and resulting disease. Such information will provide a framework for the rationale design of new treatments and measures to reduce the burden of disease. We have previously utilized the genetic variation between inbred mouse strain s to identify virologic and immunologic hallmarks of severe influenza disease. These studies provided the data supporting our hypothesis that host polymorphisms have substantial impact on influenza virus disease by modulating early viral replication kinetics. To identify the specific host genetic polymorphisms involved, we utilized the fact that the A/J mouse strain was more susceptible to H5N1 influenza virus than the C57B L/6 strain. Furthering this observation, we have now localized the genetic factors behind the increased disease in A/J mice to a single chromosome. Consomic C57BL/6 mice containing this A/ J chromosome were more susceptible to highly pathogenic H5N1 influenza A virus and influenza B virus infection as compared to C57BL/6 wild type controls. Susceptibility to H5N1 virus was associated with higher viral loads in the lungs and increased production of pro-inflammatory cytokines; all hallmarks of a severe H5N1 infection in humans. To identify the host gene responsible for the disparity in pathogenesis, we will (1) define the genetic locus associated with the increased mortality and higher viral loads using congenic mouse strains, and (2) identify the mechanism of increased viral load in the susceptible animals. Finally, we will perform candidate host gene analysis and assess their role on influenza virus infection and replication. At the conclusion of the proposed studies, we will have identified a novel host gene associated with severe influenza.

描述(申请人提供)：高致病性H5N1流感病毒继续在东南亚和非洲传播。自2003年以来，已报告550多例人感染H5N1病例，其中约50%已死亡。虽然H5N1感染者的确切人数不得而知，但已确定的感染者的疾病严重程度是由病毒和宿主因素共同决定的。有证据表明，宿主基因多态性参与了H5N1病毒的致病过程，并对其进行识别，受影响的宿主基因将揭示H5N1病毒感染和由此引起的疾病的重要生物学特性。这些信息将为设计新的治疗方法和减轻疾病负担的措施提供一个框架。我们之前已经利用近交系小鼠S之间的遗传变异来鉴定严重流感疾病的病毒学和免疫学特征。这些研究提供了支持我们的假设的数据，即宿主多态通过调节早期病毒复制动力学而对流感病毒疾病产生实质性影响。为了确定所涉及的特定宿主遗传多态，我们利用 A/J小鼠品系比C57B L/6品系对H5N1流感病毒更敏感。为了进一步观察，我们现在已经将A/J小鼠疾病增加背后的遗传因素定位到单个染色体上。结论含有该A/J染色体的C57BL/6小鼠对高致病性H5N1甲型和乙型流感病毒感染的易感性高于C57BL/6野生型对照鼠。对H5N1病毒的易感性与肺部病毒载量较高和促炎细胞因子的产生增加有关；这些都是人类严重感染H5N1病毒的特征。为了确定致病机制差异的宿主基因，我们将(1)利用同源小鼠品系定义与死亡率增加和病毒载量增加相关的遗传基因，(2)确定易感动物的病毒载量增加的机制。最后，我们会 进行候选宿主基因分析，并评估它们在流感病毒感染和复制中的作用。在拟议的研究结束时，我们将确定一个与严重流感相关的新宿主基因。