ABSTRACT

Diverse SARS-like coronaviruses (SL-CoVs) have been identified from bats and other animal species. Like SARS-CoV, some bat SL-CoVs, such as WIV1, also use angiotensin converting enzyme 2 (ACE2) from human and bat as entry receptor. However, whether these viruses can also use the ACE2 of other animal species as their receptor remains to be determined. We report herein that WIV1 has a broader tropism to ACE2 orthologs than SARS-CoV isolate Tor2. Among the 9 ACE2 orthologs examined, human ACE2 exhibited the highest efficiency to mediate the infection of WIV1 pseudotyped virus. Our findings thus imply that WIV1 has the potential to infect a wide range of wild animals and may directly jump to humans. We also showed that cell entry of WIV1 could be restricted by interferon-induced transmembrane proteins (IFITMs). However, WIV1 could exploit the airway protease TMPRSS2 to partially evade the IFITM3 restriction. Interestingly, we also found that amphotericin B could enhance the infectious entry of SARS-CoVs and SL-CoVs by evading IFITM3-mediated restriction. Collectively, our findings further underscore the risk of exposure to animal SL-CoVs and highlight the vulnerability of patients who take amphotericin B to infection by SL-CoVs, including the most recently emerging (SARS-CoV-2).

摘要

从蝙蝠和其他动物物种中已鉴定出多种SARS样冠状病毒（SL-CoV）。像SARS-CoV一样，某些蝙蝠SL-CoV（例如WIV1）也使用人类和蝙蝠的血管紧张素转化酶2（ACE2）作为进入受体。但是，这些病毒是否还可以使用其他动物的ACE2作为其受体仍有待确定。我们在本文中报道，与SARS-CoV分离株Tor2相比，WIV1与ACE2直系同源基因的同源性更广。在检查的9个ACE2直系同源物中，人ACE2表现出最高的介导WIV1假型病毒感染的效率。因此，我们的发现暗示WIV1有可能感染多种野生动物，并可能直接跳向人类。我们还表明，WIV1的细胞进入可能受到干扰素诱导的跨膜蛋白（IFITMs）的限制。然而，WIV1可以利用气道蛋白酶TMPRSS2来部分逃避IFITM3的限制。有趣的是，我们还发现两性霉素B可以通过逃避IFITM3介导的限制来增强SARS-CoV和SL-CoV的感染性。总的来说，我们的发现进一步强调了暴露于动物SL-CoV的风险，并强调了服用两性霉素B的患者易受SL-CoV感染，包括最近出现的SARS-CoV-2）。