SARS-CoV-2 infects a broader range of mammalian species than previously anticipated, suggesting there may be additional unknown hosts wherein the virus can evolve and potentially circumvent effective vaccines. We find that SARS-CoV-2 gains a wide host range by binding ACE2 sites essential for ACE2 carboxypeptidase activity. Six mutations found only in rodent species immune to SARS-CoV-2 are sufficient to abolish viral binding to human and dog ACE2. This is achieved through context-dependent mutational effects (intramolecular epistasis) conserved despite ACE2 sequence divergence between species. Across mammals, this epistasis generates sequence-function diversity, but through structures all bound by SARS-CoV-2. Mutational trajectories to the mouse conformation not bound by SARS-CoV-2 are blocked, by single mutations functionally deleterious in isolation, but compensatory in combination, explaining why human polymorphisms at these sites are virtually non-existent. Closed to humans, this path was opened to rodents via permissive cardiovascular phenotypes and ancient increases to ACE2 activity, serendipitously granting SARS-CoV-2 immunity. This reveals how ancient evolutionary trajectories are linked with unprecedented phenotypes such as COVID-19 and suggests extreme caution should be taken to monitor and prevent emerging animal reservoirs of SARS-CoV-2.

中文翻译：

---

ACE2的古老心脏保护机制赋予SARS-CoV-2广泛的宿主范围

SARS-CoV-2感染的哺乳动物种类比以前预期的要广泛，这表明可能还会有其他未知宿主在其中传播病毒并可能避开有效疫苗。我们发现，SARS-CoV-2通过结合ACE2羧肽酶活性必不可少的ACE2位点而获得了较宽的宿主范围。仅在对SARS-CoV-2免疫的啮齿动物中发现的六个突变足以消除病毒与人和狗ACE2的结合。尽管物种之间存在ACE2序列差异，但仍可通过保留上下文相关的突变效应（分子内上位）来实现这一目标。在整个哺乳动物中，这种上位产生了序列功能的多样性，但通过全部由SARS-CoV-2结合的结构。不受SARS-CoV-2约束的小鼠构象突变轨迹被阻止，单个突变在功能上是有害的，但在组合上却是补偿性的，这解释了为什么这些位点上的人类多态性实际上不存在。对人类不开放，这条途径是通过允许的心血管表型向啮齿动物开放的，并且古老地增加了ACE2的活性，偶然地赋予了SARS-CoV-2免疫力。这揭示了古代进化轨迹如何与前所未有的表型（例如COVID-19）联系在一起，并建议应格外小心，以监测和预防SARS-CoV-2的新兴动物蓄积库。