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

持续的冠状病毒病-2019（COVID-19）大流行，由一种名为 严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）与SARS冠状病毒密切相关， 严重威胁全球健康，并摧毁了世界各地的社会。COVID-19的一个令人困惑的方面是 感染者的临床表现差异显著，大多数无症状 或表现出轻微症状，以较小的，很大程度上取决于年龄的部分谁发展危及生命的条件。 不幸的是，对COVID-19易感性背后的潜在生物学知识严重不足。 可以想象，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 多样的和可复制的同基因小鼠队列代表了一种有效的方法来剖析这些宿主基因 调节微生物感染的差异。我们最近已经证明，大型企业的两个创始人 BXD小鼠家族-C57 BL/6 J（B6）和DBA/2 J（D2），在它们对小鼠的易感性方面有很大差异， SARS-CoV，MA15。鼻内激发后，D2发展为更严重的疾病并支持 比B6更持久的肺部病毒复制。在初步研究中，我们观察到类似的 当比较老年B6和D2小鼠感染小鼠适应的SARS-CoV-2病毒时， CMA 4.这些关键发现支持了使用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了宿主对SARS-CoV-2感染的反应， 从而赋予对COVID-19的不同易感性/抗性和结果。两个具体目标是 来检验这个假设。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亚组中的感染。我们将首先定义各种表型 与疾病严重程度、病原体负荷和先天免疫反应相关， B6和D2感染SARS-CoV-2 CMA 4和B.1.351（一种SARS-CoV-2患者分离株，能够 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 表型、转录组和细胞因子谱跨越不同基因型的老年BXD菌株的队列。在 目标2，我们将整合目标1的表型和转录组数据集，并将它们与目标1的表型和转录组数据集联合收割机结合。 已经获得了BXD菌株的基因型和序列数据，以绘制遗传基因座并确定候选基因 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感染的易感性。获得的新知识将有助于 针对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.