Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-06-15 , DOI: 10.1073/pnas.2102983118 Lok-Yin Roy Wong, Jian Zheng, Alan Sariol, Shea Lowery, David K. Meyerholz, Tom Gallagher, Stanley Perlman
Human Middle East respiratory syndrome (MERS) cases were detected primarily in the Middle East before a major outbreak occurred in South Korea in 2015. The Korean outbreak was initiated by a single infected individual, allowing studies of virus evolution in the absence of further MERS-CoV introduction into human populations. In contrast, MERS is primarily a camel disease on the Arabian Peninsula and in Africa, with clinical disease in humans only in the former location. Previous work identified two mutations in the South Korean MERS-CoV, D510G and I529T on the Spike (S) protein, that led to impaired binding to the receptor. However, whether these mutations affected virulence is unknown. To address this question, we constructed isogenic viruses expressing mutations found in the S protein from Korean isolates and showed that isogenic viruses carrying the Korean MERS-CoV mutations, D510G or I529T, were attenuated in mice, resulting in greater survival, less induction of inflammatory cytokines, and less severe lung injury. In contrast, isogenic viruses expressing S proteins from African isolates were nearly fully virulent; other studies showed that West African camel isolates carry mutations in MERS-CoV accessory proteins, which may limit human transmission. These data indicate that following a single-point introduction of the virus, MERS-CoV S protein evolved rapidly in South Korea to adapt to human populations, with consequences on virulence. In contrast, the mutations in S proteins of African isolates did not change virulence, indicating that S protein variation likely does not play a major role in the lack of camel-to-human transmission in Africa.
中东呼吸综合征冠状病毒 Spike 蛋白变体在毒力方面表现出地域差异 [微生物学]
人类中东呼吸综合征 (MERS) 病例主要是在 2015 年韩国发生重大疫情之前在中东发现的。韩国疫情是由单个感染者引发的，因此可以在没有进一步 MERS 的情况下研究病毒进化- CoV 引入人群。相比之下，MERS 主要是阿拉伯半岛和非洲的骆驼疾病，人类临床疾病仅发生在前者。先前的工作在韩国 MERS-CoV 中发现了两个突变，即 D510G 和 I529T 在 Spike (S) 蛋白上，导致与受体的结合受损。然而，这些突变是否影响毒力尚不清楚。为了回答这个问题，我们构建了表达在韩国分离株的 S 蛋白中发现的突变的同基因病毒，并表明携带韩国 MERS-CoV 突变 D510G 或 I529T 的同基因病毒在小鼠中减毒，从而提高存活率，减少炎症细胞因子的诱导，并且不太严重肺损伤。相比之下，表达来自非洲分离株的 S 蛋白的同基因病毒几乎是完全毒力的。其他研究表明，西非骆驼分离株携带 MERS-CoV 辅助蛋白突变，这可能会限制人类传播。这些数据表明，在单点引入病毒后，MERS-CoV S 蛋白在韩国迅速进化以适应人群，从而对毒力产生影响。相比之下，非洲分离株的 S 蛋白突变并没有改变毒力，