近日，发表在国际杂志PNAS上的一篇研究论文中，来自康奈尔大学的研究人员通过研究揭开了致死性中东呼吸综合征冠状病毒（MERS-CoV）进入宿主细胞的分子机制，该研究为开发治疗中东呼吸综合征的新型疗法提供了一定的帮助。
文章中，研究者表示，一种常见酶类-弗林蛋白酶可以激活MERS-CoV同感染宿主细胞的细胞膜进行融合并且促进MERS-CoV进入到宿主细胞中。病毒学家Gary Whittaker教授说道，在进入宿主细胞过程中的特异性位点阻断弗林蛋白酶或许就可以通过抑制病毒进入宿主细胞来帮助开发针对中东呼吸综合征的新型疗法。
冠状病毒表面具有突起蛋白，其可以被蛋白酶激活并且介导宿主细胞膜的融合，最终成功进入宿主细胞，蛋白酶在突起蛋白上激活的位点就称为切割位点；研究人员在MERS-CoV病毒表面发现了两个切割位点，其每一个位点都会被弗林蛋白酶在不同的时间进行切割，当一个新的病毒在宿主细胞装配完毕后就会脱离宿主细胞，寻找下一个新的宿主细胞进行不断繁殖。
研究者表示，我们在MERS-CoV的突起蛋白上发现了两个弗林蛋白酶的切割位点，额外的切割位点或许会促进MERS-CoV在人类和动物机体中不断扩散，而最开始的感染是在肺部进行的，尽管如此该病毒还会感染其它类型的细胞，比如免疫细胞等。MERS-CoV突变的一种方式即是通过改变其所用的激活蛋白酶，而本文研究也正揭示了复杂多变的冠状病毒如何利用切割激活的策略。
目前研究人员推测，骆驼机体中的MERS-CoV已经在两年半之前发生了突变，从而使得病毒可以感染人类；而当前病毒在人群中扩散并不是很容易。最后研究者Whittaker表示，我们希望通过后期更为深入的研究来揭示MERS-CoV的感染及发病机制，同时为开发靶向性疗法提供思路和研究依据。
Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein
Jean Kaoru Millet and Gary R. Whittaker1
Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly identified betacoronavirus causing high morbidity and mortality in humans. The coronavirus spike (S) protein is the main determinant of viral entry, and although it was previously shown that MERS-CoV S can be activated by various proteases, the details of the mechanisms of proteolytic activation of fusion are still incompletely characterized. Here, we have uncovered distinctive characteristics of MERS-CoV S. We identify, by bioinformatics and peptide cleavage assays, two cleavage sites for furin, a ubiquitously expressed protease, which are located at the S1/S2 interface and at the S2′ position of the S protein. We show that although the S1/S2 site is proteolytically processed by furin during protein biosynthesis, the S2′ site is cleaved upon viral entry. MERS-CoV pseudovirion infection was shown to be enhanced by elevated levels of furin expression, and entry could be decreased by furin siRNA silencing. Enhanced furin activity appeared to partially override the low pH-dependent nature of MERS-CoV entry. Inhibition of furin activity was shown to decrease MERS-CoV S-mediated entry, as well as infection by the virus. Overall, we show that MERS-CoV has evolved an unusual two-step furin activation for fusion, suggestive of a role during the process of emergence into the human population. The ability of MERS-CoV to use furin in this manner, along with other proteases, may explain the polytropic nature of the virus.
转载地址：http://news.bioon.com/article/6660215.html
