Cell surface receptor engagement is a critical aspect of viral infection. At low pH, binding of SARS-CoV and its ACE2 receptor has a tight interaction that catalyzes the fusion of the spike and endosomal membranes followed by genome release. Largely overlooked has been the role of neutral pH in the respiratory tract, where we find that SARS-CoV stabilizes a transition state that enhances the off-rate from its receptor. An alternative pH-switch is found in CoV-2-like coronaviruses of tropical pangolins, but with a reversed phenotype where the tight interaction with ACE2 is at neutral pH. We show that a single point mutation in pangolin-CoV, unique to CoV-2, that deletes the last His residue in their receptor binding domain perpetuates this tight interaction independent of pH. This tight bond, not present in previous respiratory syndromes, implies that CoV-2 stays bound to the highly expressed ACE2 receptors in the nasal cavity about 100 times longer than CoV. This finding supports the unfamiliar pathology of CoV-2, observed virus retention in upper respiratory tract1, longer incubation times and extended periods of shedding. Implications to combat pandemics that, like SARS-CoV-2, export evolutionarily successful strains via higher transmission rates due to retention in nasal epithelium and their evolutionary origin are discussed.

中文翻译：

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关于SARS-CoV-2滞留在上呼吸道的分子机制。

细胞表面受体的参与是病毒感染的关键方面。在低pH值下，SARS-CoV及其ACE2受体的结合具有紧密的相互作用，可催化刺突和内体膜融合，随后释放基因组。在呼吸道中性pH的作用已被广泛忽略，我们发现SARS-CoV稳定了过渡态，从而增强了其受体的失活率。在热带穿山甲的CoV-2样冠状病毒中发现了另一种pH转换，但具有反转的表型，其中在中性pH下与ACE2的紧密相互作用。我们显示，穿山甲冠状病毒CoV-2特有的单点突变会删除其受体结合域中的最后一个His残基，从而使这种紧密的相互作用不依赖于pH值。这种紧密的结合力在以前的呼吸综合征中不存在，这意味着CoV-2与鼻腔中高度表达的ACE2受体保持结合，比CoV长约100倍。这一发现支持了CoV-2的不熟悉的病理学，观察到病毒在上呼吸道中的滞留，更长的孵育时间和延长的脱落期。讨论了与大流行病（SARS-CoV-2）一样，由于保留在鼻上皮及其进化起源而通过更高的传播速率输出进化成功菌株的含义。