Mutations in the Spike Protein of Middle East Respiratory Syndrome Coronavirus Transmitted in Korea Increase Resistance to Antibody-Mediated Neutralization.
Mutations in the Spike Protein of Middle East Respiratory Syndrome Coronavirus Transmitted in Korea Increase Resistance to Antibody-Mediated Neutralization.
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DOI：
10.1128/jvi.01381-18
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发表时间：
2019-01-15
影响因子：
5.4
通讯作者：
Hoffmann M
中科院分区：
文献类型：
--
作者：
Kleine-Weber H;Elzayat MT;Wang L;Graham BS;Müller MA;Drosten C;Pöhlmann S;Hoffmann M
MERS-CoV具有大流行的潜力，重要的是要确定病毒蛋白质中可能增加病毒传播的突变。在2015年大韩民国一家大型医院爆发MERS的过程中，观察到病毒刺突蛋白中含有突变的病毒变体的传播。发现这些突变降低受体结合和病毒感染性。然而，尚不清楚它们是否也发挥前病毒作用。我们证明这些突变降低了对抗体介导的中和的敏感性，并且与表达大量病毒受体DPP 4的靶细胞的稳健感染相容。中东呼吸综合征冠状病毒（MERS-CoV）对公共卫生构成威胁。该病毒在中东流行，但可通过旅行活动传播到其他国家。一名受感染的旅行者将MERS-CoV引入韩国，导致MERS医院爆发，造成186例病例和38例死亡。MERS-CoV刺突（S）蛋白通过其受体结合结构域（RBD）与细胞蛋白DPP 4结合，并介导病毒进入靶细胞。在韩国MERS爆发期间，观察到了携带RBD突变D510 G和I529 T的病毒变体的出现和传播。与直觉相反，发现这些突变减少了DPP 4结合和病毒进入靶细胞。在这项研究中，我们调查了它们是否也发挥前病毒的作用。我们证实D510 G和I529 T的变化减少了S蛋白与DPP 4的结合，但表明这种减少仅在靶细胞上DPP 4表达较低时转化为减少的病毒进入。无论是突变调制S蛋白结合唾液酸，S蛋白激活宿主细胞蛋白酶，或抑制S蛋白驱动的干扰素诱导的跨膜蛋白进入。相反，D510 G和I529 T的变化增加了S蛋白驱动的进入对MERS患者单克隆抗体和血清中和的抵抗。这些发现表明，在韩国疫情期间传播了中和敏感性降低的MERS-CoV变体，并且负责的突变与表达高水平DPP 4的细胞的强烈感染相容。MERS-CoV具有大流行的潜力，重要的是要确定可能增加病毒传播的病毒蛋白质突变。在2015年大韩民国一家大型医院爆发MERS的过程中，观察到病毒刺突蛋白中含有突变的病毒变体的传播。发现这些突变降低受体结合和病毒感染性。然而，尚不清楚它们是否也发挥前病毒作用。我们证明这些突变降低了对抗体介导的中和的敏感性，并且与表达大量病毒受体DPP 4的靶细胞的稳健感染相容。
MERS-CoV has pandemic potential, and it is important to identify mutations in viral proteins that might augment viral spread. In the course of a large hospital outbreak of MERS in the Republic of Korea in 2015, the spread of a viral variant that contained mutations in the viral spike protein was observed. These mutations were found to reduce receptor binding and viral infectivity. However, it remained unclear whether they also exerted proviral effects. We demonstrate that these mutations reduce sensitivity to antibody-mediated neutralization and are compatible with robust infection of target cells expressing large amounts of the viral receptor DPP4. Middle East respiratory syndrome coronavirus (MERS-CoV) poses a threat to public health. The virus is endemic in the Middle East but can be transmitted to other countries by travel activity. The introduction of MERS-CoV into the Republic of Korea by an infected traveler resulted in a hospital outbreak of MERS that entailed 186 cases and 38 deaths. The MERS-CoV spike (S) protein binds to the cellular protein DPP4 via its receptor binding domain (RBD) and mediates viral entry into target cells. During the MERS outbreak in Korea, emergence and spread of viral variants that harbored mutations in the RBD, D510G and I529T, was observed. Counterintuitively, these mutations were found to reduce DPP4 binding and viral entry into target cells. In this study, we investigated whether they also exerted proviral effects. We confirm that changes D510G and I529T reduce S protein binding to DPP4 but show that this reduction only translates into diminished viral entry when expression of DPP4 on target cells is low. Neither mutation modulated S protein binding to sialic acids, S protein activation by host cell proteases, or inhibition of S protein-driven entry by interferon-induced transmembrane proteins. In contrast, changes D510G and I529T increased resistance of S protein-driven entry to neutralization by monoclonal antibodies and sera from MERS patients. These findings indicate that MERS-CoV variants with reduced neutralization sensitivity were transmitted during the Korean outbreak and that the responsible mutations were compatible with robust infection of cells expressing high levels of DPP4. IMPORTANCE MERS-CoV has pandemic potential, and it is important to identify mutations in viral proteins that might augment viral spread. In the course of a large hospital outbreak of MERS in the Republic of Korea in 2015, the spread of a viral variant that contained mutations in the viral spike protein was observed. These mutations were found to reduce receptor binding and viral infectivity. However, it remained unclear whether they also exerted proviral effects. We demonstrate that these mutations reduce sensitivity to antibody-mediated neutralization and are compatible with robust infection of target cells expressing large amounts of the viral receptor DPP4.