Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors
Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors
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DOI：
10.1099/jgv.0.001047
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发表时间：
2018-05-01
影响因子：
3.8
通讯作者：
Machamer, Carolyn E.
中科院分区：
文献类型：
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作者：
Sisk, Jeanne M.;Frieman, Matthew B.;Machamer, Carolyn E.
包膜病毒通过与细胞膜融合进入宿主细胞，这是病毒复制所需的一个步骤。冠状病毒，包括严重急性呼吸综合征冠状病毒（SARS-CoV）、中东呼吸综合征冠状病毒（MERS-CoV）和传染性支气管炎病毒（IBV），根据细胞或组织类型，在质膜处融合或使用受体介导的内吞作用并与内体融合。病毒刺突蛋白介导与宿主细胞膜的融合。我们以前已经表明，Abelson（Abl）激酶抑制剂伊马替尼，显着降低SARS-CoV和MERS-CoV病毒滴度，并防止HIV SARS S和MERS S假型病毒粒子进入内体。SARS-CoV和MERS-CoV被归类为BSL-3病毒，这使得实验感染的细胞机制更具挑战性。在这里，我们使用IBV，一种BSL-2病毒，作为研究冠状病毒感染过程中Abl激酶活性的作用的模型。我们发现伊马替尼和两种特异性Abl激酶抑制剂GNF 2和GNF 5通过阻断第一轮病毒感染来降低IBV滴度。此外，所有三种药物在半融合步骤之前防止IBV S诱导的合胞体形成。我们的研究结果表明，膜融合（病毒-细胞和细胞-细胞）的Abl激酶抑制剂的存在下被阻断。研究Abl激酶抑制剂对IBV的影响将有助于确定冠状病毒感染所需的宿主细胞途径。这将为治疗当前和新出现的冠状病毒感染提供可能的治疗靶点。
Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type. The virus spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abelson (Abl) kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titres and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions. SARS-CoV and MERS-CoV are classified as BSL-3 viruses, which makes experimentation into the cellular mechanisms involved in infection more challenging. Here, we use IBV, a BSL-2 virus, as a model for studying the role of Abl kinase activity during coronavirus infection. We found that imatinib and two specific Abl kinase inhibitors, GNF2 and GNF5, reduce IBV titres by blocking the first round of virus infection. Additionally, all three drugs prevented IBV S-induced syncytia formation prior to the hemifusion step. Our results indicate that membrane fusion (both virus-cell and cell-cell) is blocked in the presence of Abl kinase inhibitors. Studying the effects of Abl kinase inhibitors on IBV will be useful in identifying the host cell pathways required for coronavirus infection. This will provide an insight into possible therapeutic targets to treat infections by current as well as newly emerging coronaviruses.