Host genetic determinants regulating susceptibility/resistance to SARS-CoV-2

调节 SARS-CoV-2 易感性/耐药性的宿主遗传决定因素

• 批准号: 10625449
• 负责人: KUI LI
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625449
• 关键词: 2019-nCoV; Age; Biology; Body Weight decreased; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 severity; COVID-19 susceptibility; Candidate Disease Gene; Caring; Chromosome Mapping; Clinical; Complex; Coronavirus; Coronavirus Infections; Data; Data Set; Development; Disease; Disease Progression; Disease susceptibility; Elderly; Exhibits; Family; Genes; Genetic; Genetic Determinism; Genotype; Goals; Health; Health Professional; Healthcare; Hospitals; Immune response; Inbred C57BL Mice; Inbreeding; Individual; Infection; Innate Immune Response; Intervention; Knowledge; Life; Lung; Measurable Disease; Molecular; Mus; Outcome; Parents; Pathogenesis; Pathogenicity; Pathway interactions; Patient Isolation; Patients; Phenotype; Play; Population; Predisposition; Public Health; Recombinants; Reporting; Resistance; Resources; Risk; SARS coronavirus; SARS-CoV-2 B.1.351; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; Severe Acute Respiratory Syndrome; Severity of illness; Societies; Symptoms; System; Testing; Therapeutic; Variant; Viral; Virus; Virus Diseases; Virus Replication; Wild Type Mouse; age related; aged; candidate identification; cohort; cytokine; epidemiology study; genetic analysis; genetic makeup; genomic locus; global health; human coronavirus; influenzavirus; insight; microbial; novel; novel coronavirus; pathogen; prophylactic; segregation; targeted treatment; transcriptome; transcriptomics; virus host interaction

The ongoing coronavirus disease-2019 (COVID-19) pandemic, caused by a novel coronavirus (CoV) termed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that is closely related to SARS-CoV, poses a grave threat to global health, and has devastated societies worldwide. One puzzling aspect of COVID-19 is the impressive variation in clinical manifestations among infected individuals, from a majority who are asymptomatic or exhibit mild symptoms to a smaller, largely age-dependent fraction who develop life-threatening conditions. Unfortunately, knowledge of the underlying biology behind COVID-19 susceptibility is woefully inadequate. Conceivably, some of the differences are likely the consequence of host genetic factors. Systems genetics using diverse and replicable cohorts of isogenic mice represents a powerful way to dissect those host genetic differences that modulate microbial infections. We have recently demonstrated that the two founders of the large BXD family of mice — C57BL/6J (B6) and DBA/2J (D2), differ substantially in their susceptibility to a mouse- adapted SARS-CoV, MA15. Following intranasal challenge, D2 develop a more severe disease and support more prolonged pulmonary viral replication than B6. In preliminary studies, we have observed a similar phenomenon when comparing aged B6 and D2 mice for infection by a mouse-adapted SARS-CoV-2 virus, CMA4. These key findings support the practicality of using the BXD family of mice to systemically dissect virus- host interactions that modulate sensitivity to and disease progression of SARS-CoV or SARS-CoV-2 infection. We hypothesize that variations in host genetic makeup regulate the host responses to SARS-CoV-2 infection, thereby imparting differing susceptibility/resistance to and outcome of COVID-19. Two specific aims are proposed to test this hypothesis. In Aim 1, we will determine the impact of genetic background on SARS-CoV-2 infection in the parental strains and across a subset of ~30 BXDs. We will first define the various phenotypes associated with disease severity, pathogen load, and innate immune responses that distinguish between aged B6 and D2 following infection with SARS-CoV-2 CMA4 and B.1.351 (a SARS-CoV-2 patient isolate capable of replication in wild-type mice), respectively. We will then characterize these measurable disease-state phenotypes, transcriptome and cytokine profiles across a cohort of aged BXD strains of diverse genotypes. In Aim 2, we will integrate the phenotypic and transcriptomic datasets from Aim 1 and combine them with the already acquired genotypes and sequence data for the BXD strains to map genetic loci and define the candidate genes and molecular networks that regulate SARS-CoV-2 replication and pathogenesis. Data from these studies will uncover novel insights into age-independent host genetic factors that modulate viral replication and disease susceptibility during SARS-CoV-2 infection. The new knowledge gained will aid the development of countermeasures against SARS-CoV-2 and possibly other pathogenic human CoV infections.

正在进行的 2019 冠状病毒病 (COVID-19) 大流行，由一种称为 严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2) 与 SARS-CoV 密切相关， 对全球健康构成严重威胁，并给全世界社会带来破坏。 COVID-19 的一个令人费解的方面是 感染者（大多数无症状）的临床表现存在显着差异 或者一小部分人表现出轻微症状，很大程度上取决于年龄，他们会出现危及生命的状况。 不幸的是，我们对 COVID-19 易感性背后的基础生物学知识还远远不够。 可以想象，一些差异可能是宿主遗传因素的结果。系统遗传学使用 多样化且可复制的同基因小鼠群体代表了剖析宿主遗传的有效方法 调节微生物感染的差异。我们最近证明了这家大型公司的两位创始人 BXD 小鼠家族 — C57BL/6J (B6) 和 DBA/2J (D2) 在对小鼠- 适应了 SARS-CoV，MA15。鼻内攻击后，D2 出现更严重的疾病并支持 比 B6 更长时间的肺部病毒复制。在初步研究中，我们观察到类似的情况 比较老年 B6 和 D2 小鼠感染适应小鼠的 SARS-CoV-2 病毒时出现的现象， CMA4。这些关键发现支持使用 BXD 小鼠家族系统解剖病毒的实用性 调节 SARS-CoV 或 SARS-CoV-2 感染的敏感性和疾病进展的宿主相互作用。 我们假设宿主基因组成的变化调节宿主对 SARS-CoV-2 感染的反应， 从而对 COVID-19 产生不同的易感性/抵抗力和结果。两个具体目标是 建议检验这一假设。在目标 1 中，我们将确定遗传背景对 SARS-CoV-2 的影响 亲本菌株和约 30 个 BXD 子集的感染。我们首先定义各种表型 与疾病严重程度、病原体负荷和区分老年人的先天免疫反应有关 感染 SARS-CoV-2 CMA4 和 B.1.351 后的 B6 和 D2（一种 SARS-CoV-2 患者分离株，能够 分别在野生型小鼠中复制）。然后我们将描述这些可测量的疾病状态 一组不同基因型的老年 BXD 菌株的表型、转录组和细胞因子谱。在 目标 2，我们将整合目标 1 的表型和转录组数据集，并将它们与 已经获得 BXD 菌株的基因型和序列数据，以绘制遗传位点图并定义候选菌株 调节 SARS-CoV-2 复制和发病机制的基因和分子网络。这些研究的数据 将揭示调节病毒复制和疾病的与年龄无关的宿主遗传因素的新见解 SARS-CoV-2 感染期间的易感性。获得的新知识将有助于发展 针对 SARS-CoV-2 和可能的其他致病性人类 CoV 感染的对策。