Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus
Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus
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DOI：
10.1073/pnas.1405889111
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发表时间：
2014-08-26
影响因子：
11.1
通讯作者：
Li, Fang
中科院分区：
文献类型：
--
作者：
Yang, Yang;Du, Lanying;Li, Fang
中东呼吸综合征冠状病毒（MERS-CoV）目前在人类中传播，在受感染患者中造成类似36%的死亡率。中东呼吸综合征冠状病毒据信起源于蝙蝠，与蝙蝠冠状病毒HKU4和HKU5有遗传关系。为了了解蝙蝠冠状病毒如何传播给人类，我们研究了HKU4和HKU5病毒表面刺突蛋白的受体使用和细胞进入活性。我们发现MERS-CoV的受体二肽基肽酶4 （DPP4）也是HKU4的受体，但不是HKU5的受体。尽管共享一个共同的受体，MERS-CoV和HKU4刺突表现出功能差异。首先，MERS-CoV更倾向于人类DPP4而不是蝙蝠DPP4作为受体，而HKU4表现出相反的趋势。其次，在缺乏外源性蛋白酶的情况下，MERS-CoV和HKU4刺突都介导假病毒进入蝙蝠细胞，而只有MERS-CoV刺突介导假病毒进入人类细胞，而HKU4刺突不介导。因此，MERS-CoV，而不是HKU4，已经适应了利用人类DPP4和人类细胞蛋白酶来有效地进入人类细胞，这有助于增强MERS-CoV在人类中的发病机制。这些结果表明DPP4是HKU4的功能性受体，而宿主细胞蛋白酶是HKU4的宿主范围决定因素。他们还认为，识别dpp4的蝙蝠冠状病毒威胁着人类健康，因为它们的尖刺能够适应人类细胞进行跨物种传播。
Middle East respiratory syndrome coronavirus (MERS-CoV) currently spreads in humans and causes similar to 36% fatality in infected patients. Believed to have originated from bats, MERS-CoV is genetically related to bat coronaviruses HKU4 and HKU5. To understand how bat coronaviruses transmit to humans, we investigated the receptor usage and cell entry activity of the virus-surface spike proteins of HKU4 and HKU5. We found that dipeptidyl peptidase 4 (DPP4), the receptor for MERS-CoV, is also the receptor for HKU4, but not HKU5. Despite sharing a common receptor, MERS-CoV and HKU4 spikes demonstrated functional differences. First, whereas MERS-CoV prefers human DPP4 over bat DPP4 as its receptor, HKU4 shows the opposite trend. Second, in the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediate pseudovirus entry into bat cells, whereas only MERS-CoV spike, but not HKU4 spike, mediates pseudovirus entry into human cells. Thus, MERS-CoV, but not HKU4, has adapted to use human DPP4 and human cellular proteases for efficient human cell entry, contributing to the enhanced pathogenesis of MERS-CoV in humans. These results establish DPP4 as a functional receptor for HKU4 and host cellular proteases as a host range determinant for HKU4. They also suggest that DPP4-recognizing bat coronaviruses threaten human health because of their spikes' capability to adapt to human cells for cross-species transmissions.