Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18- hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding anti-coronavirus immunity.

中文翻译：

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SARS-CoV-2 感染的遗传多样性小鼠模型再现了 COVID-19 中 I 型干扰素和细胞因子反应的临床变异

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 感染引起的炎症会导致 2019 冠状病毒病 (COVID-19) 的严重程度，并受宿主遗传学的影响。为了了解炎症的机制，需要反映遗传多样性和在人类中观察到的临床结果的动物模型。我们报告了一个小鼠面板，其中包含与人类 ACE2 转基因小鼠 (K18-hACE2) 杂交的具有遗传多样性的协同杂交 (CC) 创始菌株，该小鼠赋予对 SARS-CoV-2 的易感性。CC x K18-hACE2 的感染导致一系列生存、病毒复制动力学和免疫概况。重要的是，与 K18-hACE2 模型相比，在对疾病具有高度抵抗力的 PWK x K18-hACE2 小鼠中，需要早期 I 型干扰素 (IFN-I) 和受调节的促炎反应来控制 SARS-CoV-2 的复制。因此，可以在不同的小鼠品系中对 COVID-19 中观察到的病毒动力学和炎症进行建模，从而为了解抗冠状病毒免疫提供了一个遗传上易于处理的平台。