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: 10510620
• 负责人: KUI LI
• 金额: $ 23.1万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510620
• 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; 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; Maps; Measurable Disease; Molecular; Mus; Outcome; Parents; Pathogenesis; Pathogenicity; Pathway interactions; Patient Isolators; Patients; Phenotype; Play; Population; Predisposition; Public Health; Recombinants; Reporting; Resistance; Resources; Risk; SARS coronavirus; SARS-CoV-2 B.1.351; Severe Acute Respiratory Syndrome; Severity of illness; Societies; Symptoms; System; Testing; Therapeutic; Time; Variant; Viral; Virus; Virus Diseases; Virus Replication; Wild Type Mouse; age related; aged; cohort; cytokine; epidemiology study; genetic analysis; genetic makeup; genomic locus; global health; human coronavirus; influenzavirus; insight; microbial; novel; novel coronavirus; pathogen; prophylactic; 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.

持续的冠状病毒疾病-2019（COVID-19）大流行，由一种新的冠状病毒（COV）造成 与SARS-COV密切相关的严重急性呼吸综合征2（SARS-COV-2） 对全球健康的严重威胁，并在全球拥有毁灭性的社会。 COVID-19的一个拼图者是 来自大多数无症状的受感染个体的临床表现的令人印象深刻的差异 或将轻度症状暴露于较小的，很大程度上依赖年龄的症状，这些症状发展危及生命的状况。 不幸的是，了解Covid-19易感性背后的潜在生物学是不足的。 可以想象，某些差异可能是宿主遗传因素的结果。系统遗传学使用 潜水员和可复制的同源小鼠的人群代表了一种剖析那些宿主遗传的有力方法 调节微生物感染的差异。我们最近证明了大型的两个创始人 BXD小鼠家族 - C57BL/6J（B6）和DBA/2J（D2），它们对小鼠的敏感性有很大不同 改编的SARS-COV，MA15。在鼻内挑战之后，D2发展出更严重的疾病和支持 比B6更长时间的肺病毒复制。在初步研究中，我们观察到类似的 现象当比较老年B6和D2小鼠以通过小鼠适应的SARS-COV-2病毒感染的现象时， CMA4。这些关键发现支持使用BXD小鼠家族系统地剖析病毒的实用性。 宿主相互作用，调节SARS-COV或SARS-COV-2感染的敏感性和疾病进展。 我们假设宿主遗传构成的变化调节宿主对SARS-COV-2感染的反应， 从而赋予了Covid-19的敏感性/抵抗力和结果。两个具体目标是 提议检验这一假设。在AIM 1中，我们将确定遗传背景对SARS-COV-2的影响 父母菌株的感染以及约30 BXD的子集。我们将首先定义各种表型 与疾病的严重程度，病原体负荷和先天免疫反应相关 SARS-COV-2 CMA4和B.1.351感染后B6和D2（SARS-COV-2患者分离株能够 分别在野生型小鼠中复制）。然后，我们将表征这些可测量的疾病状态 各种基因型的老年BXD菌株跨越表型，转录组和细胞因子谱。 AIM 2，我们将从AIM 1整合表型和转录数据集，并将其与 BXD菌株已经获得了基因型和序列数据，以绘制遗传基因座并定义候选者 调节SARS-COV-2复制和发病机理的基因和分子网络。这些研究的数据 将发现对与年龄无关的宿主遗传因素的新见解，这些遗传因素调节病毒复制和疾病 SARS-COV-2感染期间的敏感性。获得的新知识将有助于发展 针对SARS-COV-2以及可能其他病原的人类COV感染的对策。