Wang Ningning, Ji Weiwei, Jiao Houqi, Veit Michael, Sun Ju, Wang Yanjun, Ma Xing, Wang Yu, Wang Yutong, Li Xin-Xin, Zhang Xiaoguang, Chen Jie, Wei Jiayu, Xu Ying, Guo Dawei, Zhai Xiaofeng, Merits Andres, Li Chang, Rey Félix A, Dobrikov Georgi M, Gao George F, Zhang Shuijun, Bi Yuhai, Su Shuo
Academy for Advanced Interdisciplinary Studies, College of Veterinary Medicine, Engineering Laboratory of Animal Immunity of Jiangsu Province, Nanjing Agricultural University, Nanjing, China.
College of Life Sciences, Nanjing Agricultural University, Nanjing, China.
Nature. 2025 Jun;642(8068):739-746. doi: 10.1038/s41586-025-09007-w. Epub 2025 Apr 30.
Despite accumulating evidence that bat-derived coronaviruses often require intermediate hosts to facilitate transmission to humans, the potential role of fur animals in zoonotic coronavirus spillovers has largely been overlooked. Here we report the isolation and characterization of a previously undescribed mink respiratory coronavirus (MRCoV) from farmed minks with pneumonia. Notably, MRCoV uses angiotensin-converting enzyme 2 (ACE2) as an entry receptor and can infect mink, bat, monkey and human cells. Cryo-electron microscopy analyses revealed that the MRCoV receptor-binding domain (RBD) binds to the same interface on ACE2 receptors as the RBD of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) despite structural differences. We identify the key determinants on the RBD of MRCoV and ACE2 that confer efficient binding. HKU5-33S, a bat coronavirus closely related to MRCoV, uses ACE2 of the bat Pipistrellus abramus for cell entry and requires only two amino acid substitutions to adapt to mink ACE2. SARS-CoV-2 protease and polymerase inhibitors potently block MRCoV infection, thereby indicating a potential therapeutic strategy. Collectively, these findings enhance our understanding of coronavirus receptor dynamics and highlight their zoonotic potential. Given the risks posed by fur farms as reservoirs for emerging pathogens, our study underscores the need for enhanced surveillance to mitigate future coronavirus outbreaks.
尽管越来越多的证据表明，源自蝙蝠的冠状病毒通常需要中间宿主来促进向人类的传播，但毛皮动物在人畜共患冠状病毒溢出事件中的潜在作用在很大程度上被忽视了。在此，我们报告了从患有肺炎的养殖水貂中分离并鉴定出一种此前未被描述的水貂呼吸道冠状病毒（MRCoV）。值得注意的是，MRCoV利用血管紧张素转换酶2（ACE2）作为进入受体，并且可以感染水貂、蝙蝠、猴子和人类细胞。冷冻电子显微镜分析显示，尽管结构存在差异，但MRCoV的受体结合域（RBD）与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的RBD在ACE2受体上结合于相同界面。我们确定了MRCoV和ACE2的RBD上赋予有效结合的关键决定因素。与MRCoV密切相关的蝙蝠冠状病毒HKU5-33S利用伏翼蝙蝠的ACE2进入细胞，并且只需要两个氨基酸替换就能适应水貂ACE2。SARS-CoV-2蛋白酶和聚合酶抑制剂能有效阻断MRCoV感染，从而表明了一种潜在的治疗策略。总体而言，这些发现增进了我们对冠状病毒受体动态变化的理解，并突出了它们的人畜共患潜力。鉴于毛皮养殖场作为新出现病原体宿主所带来的风险，我们的研究强调需要加强监测以减轻未来冠状病毒的爆发。
