So Ray Ty, Chu Daniel Kw, Hui Kenrie Py, Mok Chris Kp, Sanyal Sumana, Nicholls John M, Ho John C W, Cheung Man-Chun, Ng Ka-Chun, Yeung Hin-Wo, Chan Michael Cw, Poon Leo Lm, Zhao Jincun, Peiris Malik
School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China.
HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.
bioRxiv. 2023 Mar 28:2023.03.27.534490. doi: 10.1101/2023.03.27.534490.
Middle East respiratory syndrome coronavirus (MERS-CoV) causes zoonotic disease. Dromedary camels are the source of zoonotic infection. We identified a mutation of amino acid leucine to phenylalanine in the codon 232 position of the non-structural protein 6 (nsp6) (nsp6 L232F) that is repeatedly associated with zoonotic transmission. We generated a pair of isogenic recombinant MERS-CoV with nsp6 232L and 232F residues, respectively, and showed that the nsp6 L232F mutation confers higher replication competence in ex-vivo culture of human nasal and bronchial tissues and in lungs of mice experimentally infected in-vivo. Mechanistically, the nsp6 L232F mutation appeared to modulate autophagy and was associated with higher exocytic virus egress, while innate immune responses and zippering activity of the endoplasmic reticulum remained unaffected. Our study suggests that MERS-CoV nsp6 may contribute to viral adaptation to humans. This highlights the importance of continued surveillance of MERS-CoV in both camels and humans.
中东呼吸综合征冠状病毒（MERS-CoV）可引发人畜共患病。单峰骆驼是这种人畜共患感染的源头。我们在非结构蛋白6（nsp6）的第232位密码子处发现了一个从亮氨酸到苯丙氨酸的氨基酸突变（nsp6 L232F），该突变反复与人畜共患传播相关。我们分别构建了一对携带nsp6 232L和232F残基的同基因重组MERS-CoV，并表明nsp6 L232F突变在人鼻和支气管组织的体外培养以及实验性体内感染小鼠的肺部中赋予了更高的复制能力。从机制上讲，nsp6 L232F突变似乎调节了自噬，并与更高的胞吐病毒释放相关，而先天免疫反应和内质网的拉链活性未受影响。我们的研究表明，MERS-CoV nsp6可能有助于病毒适应人类。这凸显了持续监测骆驼和人类中MERS-CoV的重要性。
