Systems Immunogenetics of Biodefense and Emerging Pathogens in the Collaborative Cross

生物防御和新兴病原体协同交叉的系统免疫遗传学

• 批准号: 10265701
• 负责人: Ralph S Baric
• 金额: $ 9.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265701
• 关键词: Affect; Antiviral Agents; Autoimmunity; Automobile Driving; Biological Models; Clustered Regularly Interspaced Short Palindromic Repeats; Data Set; Databases; Diagnosis; Disease; Environmental Risk Factor; Ethics; Gene Combinations; Genes; Genetic; Genetic Variation; Health; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immunity; Immunogenetics; Inbreeding; Individual; Infection; Inflammation; Influenza A virus; Maps; Mediating; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Pathogenesis; Pathologic; Pathway interactions; Phenotype; Play; Population; Quantitative Genetics; Quantitative Trait Loci; Recombinants; Reproducibility; Research; Research Design; Role; SARS coronavirus; Sampling; Shapes; Signal Pathway; System; Testing; Therapeutic Intervention; Time; Variant; Viral Pathogenesis; Virus; Virus Diseases; West Nile virus; adaptive immunity; biodefense; cohort; emerging pathogen; genome editing; genomic locus; mortality; mouse genetics; pathogenic virus; preventive intervention; programs; respiratory virus; response; therapeutic target; tool; vaccine efficacy; vaccine safety

Abstract: Emerging viruses, such as SARS-CoV, influenza A virus (IAV), and West Nile virus (WNV) cause high levels of morbidity and mortality in human populations. Host immune responses can play either protective or a pathologic role during viral infections. Therefore, understanding of the regulatory networks and signaling pathways that determine the magnitude and quality of an individual's antiviral immune response has important implications for human health, since these genes/pathways could be therapeutically targeted to treat virus- induced disease, or may represent targets for enhancing the safety and efficacy of vaccines against a wide range of viral pathogens. Polymorphic host genes and regulatory networks have a major impact on immune response variation in human populations. However, confounding environmental factors and/or ethical concerns limit the types of studies that can be conducted in humans. Therefore, genetically tractable model systems that capture the range of genetic and phenotypic diversity seen in humans, such as the Collaborative Cross (CC) are needed to mechanistically dissect the genetics of immune variation. Our research team has quantified variation in baseline, as well as SARS-CoV, IAV, and WNV-induced immune responses in a panel of 110 CC RIX lines (reproducible F1 crosses between CC recombinant inbred (RI) lines that model heterozygous human populations). To our knowledge, this represents to most comprehensive analysis of immune response variation ever conducted in a genetic reference population, and in ongoing QTL mapping studies, we have identified 100+ quantitative trait loci (QTL) associated with variation in virus-induced innate and adaptive immunity, inflammation and disease. Our program, which includes expertise in viral pathogenesis, innate and adaptive immunity, and quantitative genetics will use this unprecedented data base to: 1) identify and characterize polymorphic host genes that drive variation in virus-induced disease, 2) test how interactions between different polymorphic genes/loci shape the host immune response, 3) test how these genes impact responses to other viral pathogens, or function during allergy/auto-immunity, and 4) test the impact of these genes in the context of human infections to identify targets for diagnosis, prevention and therapeutic interventions in humans. These studies will significantly enhance our understanding of how host genetic variation shapes virus-induced immunity and/or disease.

翻译后摘要：新兴的病毒，如SARS冠状病毒，甲型流感病毒（IAV），西尼罗河病毒（WNV）的原因 人口发病率和死亡率高。宿主的免疫反应既可以起到保护作用， 或在病毒感染过程中的病理作用。因此，了解监管网络和信号 决定个体抗病毒免疫应答的大小和质量的途径具有重要的 对人类健康的影响，因为这些基因/途径可以在治疗上靶向治疗病毒- 诱导的疾病，或可能代表用于增强疫苗针对广泛的 一系列病毒病原体。 多态性宿主基因和调节网络对人类免疫反应变异产生重大影响 人口。然而，混杂的环境因素和/或伦理问题限制了研究的类型 可以在人类身上进行的实验。因此，遗传上易于处理的模型系统，捕捉的范围， 人类的遗传和表型多样性，如协作杂交（CC）， 机械地剖析免疫变异的遗传学。我们的研究团队已经量化了 基线，以及SARS-CoV，IAV和WNV诱导的免疫应答，在一组110个CC RIX系中 （在CC重组近交（RI）系之间的可再现的F1杂交，所述CC重组近交（RI）系模拟杂合人类 人口）。据我们所知，这代表了对免疫应答变化的最全面的分析 在遗传参考群体中进行的，以及正在进行的QTL定位研究中，我们已经确定了 100多个与病毒诱导的先天性和适应性免疫变异相关的数量性状基因座（QTL）， 炎症和疾病。我们的计划，其中包括病毒发病机制，先天和适应性的专业知识 免疫学和数量遗传学将使用这一前所未有的数据库：1）识别和表征 多态性宿主基因驱动病毒诱导的疾病的变化，2）测试不同之间的相互作用 多态性基因/基因座塑造宿主免疫应答，3）测试这些基因如何影响对其他免疫应答的反应， 病毒病原体，或在过敏/自身免疫过程中的功能，以及4）测试这些基因在背景下的影响 以确定人类诊断、预防和治疗干预的目标。 这些研究将显著增强我们对宿主遗传变异如何塑造病毒诱导的 免疫和/或疾病。

项目成果

Viral metagenomics, protein structure, and reverse genetics: Key strategies for investigating coronaviruses.

病毒宏基因组学、蛋白质结构和反向遗传学：研究冠状病毒的关键策略。

• DOI: 10.1016/j.virol.2017.12.009
• 发表时间: 2018-04
• 期刊: Virology
• 影响因子: 3.7
• 作者: Johnson BA;Graham RL;Menachery VD
• 通讯作者: Menachery VD

MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis.

MERS-COV辅助ORF在感染和发病机理中起关键作用。

• DOI: 10.1128/mbio.00665-17
• 发表时间: 2017-08-22
• 期刊: mBio
• 影响因子: 6.4
• 作者: Menachery VD;Mitchell HD;Cockrell AS;Gralinski LE;Yount BL Jr;Graham RL;McAnarney ET;Douglas MG;Scobey T;Beall A;Dinnon K 3rd;Kocher JF;Hale AE;Stratton KG;Waters KM;Baric RS
• 通讯作者: Baric RS

Genetic diversity in the collaborative cross model recapitulates human West Nile virus disease outcomes.

• DOI: 10.1128/mbio.00493-15
• 发表时间: 2015-05-05
• 期刊: mBio
• 影响因子: 6.4
• 作者: Graham JB;Thomas S;Swarts J;McMillan AA;Ferris MT;Suthar MS;Treuting PM;Ireton R;Gale M Jr;Lund JM
• 通讯作者: Lund JM

Of mice and men: the host response to influenza virus infection.

• DOI: 10.1007/s00335-018-9750-y
• 发表时间: 2018-08
• 期刊: Mammalian genome : official journal of the International Mammalian Genome Society
• 作者: Kollmus H;Pilzner C;Leist SR;Heise M;Geffers R;Schughart K
• 通讯作者: Schughart K

A Reverse Genetics Platform That Spans the Zika Virus Family Tree.

• DOI: 10.1128/mbio.02014-16
• 发表时间: 2017-03-07
• 期刊: mBio
• 影响因子: 6.4
• 作者: Widman DG;Young E;Yount BL;Plante KS;Gallichotte EN;Carbaugh DL;Peck KM;Plante J;Swanstrom J;Heise MT;Lazear HM;Baric RS
• 通讯作者: Baric RS