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

正在进行的冠状病毒病-2019年(新冠肺炎)大流行，由一种名为 与SARS冠状病毒密切相关的SARS冠状病毒2(SARS-CoV-2)构成了 对全球健康构成严重威胁，并摧毁了世界各地的社会。新冠肺炎的一个令人费解的方面是 感染者的临床表现差异很大，从大多数没有症状的人 或表现出轻微症状到较小的、主要依赖于年龄的一小部分人，他们会出现危及生命的情况。 不幸的是，对新冠肺炎易感性背后的潜在生物学知识严重不足。 可以想见，其中一些差异可能是宿主遗传因素的结果。系统遗传学使用 多样化和可复制的等基因小鼠队列是剖析这些宿主基因的有效方法 调节微生物感染的差异。我们最近已经证明，大型 BxD家族小鼠-C57BL/6J(B6)和DBA/2J(D2)-对小鼠的易感性有很大不同- 适应SARS冠状病毒，MA15。在鼻腔挑战之后，D2会发展成更严重的疾病和支持 肺病毒复制时间比B6长。在初步研究中，我们观察到了类似的 比较老年B6和D2小鼠感染小鼠适应的SARS-CoV-2病毒时的现象， CMA4.这些关键发现支持了使用BXD系列小鼠系统剖析病毒的实用性。 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， 从而赋予新冠肺炎不同的易感性/抵抗力和结局。两个具体目标是 提出用来检验这一假说。在目标1中，我们将确定遗传背景对SARS-CoV-2的影响 在亲本菌株和约30个BXD子集上的感染。我们将首先定义各种表型 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(SARS-CoV-2患者分离株能够 野生型小鼠的复制)。然后我们将描述这些可测量的疾病状态 不同基因类型的老年BXD菌株的表型、转录组和细胞因子谱。在……里面 目标2，我们将整合来自目标1的表型和转录数据集，并将它们与 已经获得的BXD菌株的基因类型和序列数据，以绘制遗传座位图并确定候选基因 调控SARS-CoV-2复制和发病机制的基因和分子网络。来自这些研究的数据 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感染时的易感性。获得的新知识将有助于……的发展 预防SARS-CoV-2和可能的其他致病性人类CoV感染的对策。

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.