Fibronectin Facilitates Enterovirus 71 Infection by Mediating Viral Entry
Fibronectin Facilitates Enterovirus 71 Infection by Mediating Viral Entry
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纤连蛋白通过介导病毒进入促进肠道病毒 71 感染。
DOI：
10.1128/jvi.02251-17
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发表时间：
2018-05-01
影响因子：
5.4
通讯作者：
Zhu, Ying
中科院分区：
文献类型：
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作者：
He, Qiao-qiao;Ren, Sheng;Zhu, Ying
纤连蛋白（FN）是一种高分子量的细胞外基质蛋白，含有RGDS基序，其是结合整合素所必需的。据报道，合成的RGDS肽与FN竞争结合细胞表面并抑制FN的功能。在此，我们鉴定了合成的RGDS肽显著抑制细胞培养物中的人肠道病毒71（EV71）感染。此外，用RGDS肽处理并感染EV71的小鼠比对照组具有显著更高的存活率和更低的病毒载量。由于RGDS肽影响FN的功能，我们质疑FN是否可能在病毒感染中发挥作用。我们的研究表明FN的过表达增强了EV71的感染。相反，FN的敲除显著降低了病毒产量并降低了病毒与宿主细胞的结合。此外，EV 71进入，而不是细胞内病毒复制，被FN抑制剂预处理阻断。接着，我们发现FN可以与EV71衣壳蛋白VP1相互作用，进一步的截短突变实验表明FN的D2结构域可以与VP1的N端片段相互作用。综上所述，我们的结果表明宿主因子FN结合EV71颗粒并促进EV71进入，为EV71感染提供了潜在的治疗靶点。近年来，手足口病疫情频繁发生，有时会导致严重的神经系统并发症，甚至导致全球婴幼儿死亡。不幸的是，没有有效的抗病毒药物可用于人类肠道病毒71（EV71），这是导致手足口病的病毒之一。尽管已经鉴定了几种受体，但感染过程和所涉及的宿主因素仍然未知。在这项研究中，我们发现宿主因子纤连蛋白（FN）通过与EV71颗粒相互作用促进EV71的复制，并进一步介导它们的进入。RGDS肽，一种FN抑制剂，显著抑制RD细胞和小鼠中的EV71复制。总之，我们的研究确定了一个新的宿主因子参与EV71感染，为EV71治疗提供了一个新的潜在抗病毒靶点。
Fibronectin (FN) is a high-molecular-weight extracellular matrix protein that contains the RGDS motif, which is required to bind to integrins. Synthetic RGDS peptides have been reported to compete with FN to bind to the cell surface and inhibit the function of FN. Here, we identified that synthetic RGDS peptides significantly inhibit human enterovirus 71 (EV71) infection in cell cultures. In addition, mice treated with RGDS peptides and infected with EV71 had a significantly higher survival rate and a lower viral load than the control group. Because RGDS peptides affect the function of FN, we questioned whether FN may play a role in virus infection. Our study indicates that overexpression of FN enhanced EV71 infection. In contrast, knockout of FN significantly reduced viral yield and decreased the viral binding to host cells. Furthermore, EV71 entry, rather than intracellular viral replication, was blocked by FN inhibitor pretreatment. Next, we found that FN could interact with the EV71 capsid protein VP1, and further truncated-mutation assays indicated that the D2 domain of FN could interact with the N-terminal fragment of VP1. Taken together, our results demonstrate that the host factor FN binds to EV71 particles and facilitates EV71 entry, providing a potential therapy target for EV71 infection. IMPORTANCE Hand, foot, and mouth disease outbreaks have occurred frequently in recent years, sometimes causing severe neurological complications and even death in infants and young children worldwide. Unfortunately, no effective antiviral drugs are available for human enterovirus 71 (EV71), one of the viruses that cause hand, foot, and mouth disease. The infection process and the host factors involved remain unknown, although several receptors have been identified. In this study, we found that the host factor fibronectin (FN) facilitated EV71 replication by interacting with EV71 particles and further mediated their entry. The RGDS peptide, an FN inhibitor, significantly inhibited EV71 replication in both RD cells and mice. In conclusion, our research identified a new host factor involved in EV71 infection, providing a new potential antiviral target for EV71 treatment.