吴建国教授团队发现肠道病毒诱导炎症反应和免疫应答的新机制
导语近日，武汉大学病毒学国家重点实验室吴建国教授团队年初在国际知名期刊PLoS Pathogens 再次发表最新科研成果：肝细胞生长调节因子酪氨酸激酶蛋白底物（HRS）在EV71激活TLR7信号通路中起关键作用。成功揭示了EV71感染引起宿主炎症反应和免疫应答的新机制。
肠道病毒71型（EV71）感染通常导致婴幼儿的手足口病（HFMD），少数重症患儿可发生无菌性脑膜炎、脑干脑炎、神经源性肺水肿等并发症，极少数患者病情危重、甚至死亡。但是，EV71引起炎症反应、免疫应答及导致疾病的机制尚未完全阐明。2017年8月30日，吴建国团队在最新一期的PLoS Pathogens杂志上在线发表文章“HRS plays an important role for TLR7 signaling to orchestrate inflammation and innate immunity upon EV71 infection”，进一步揭示了EV71感染诱导宿主炎症反应和免疫应答的新机制。该论文的共同通讯作者为吴建国教授、刘映乐副教授和刘芳副教授，第一作者为罗震博士。
该研究首先通过临床标本分析发现在EV71感染的病人血清中，炎症因子IL-1b及IL-6的表达水平显著高于正常组；并且在EV71感染的小鼠模型和巨噬细胞中证明EV71感染能激活炎症因子产生。由于Toll样受体（TLRs）介导的病原体识别能诱导宿主免疫应答和炎症反应，该团队通过信号通路抑制剂筛选及基因敲除小鼠研究，证实了EV71通过调控TLR7激活NF-κB/p38 MAPK信号通路、从而促进炎症因子表达。进一步利用siRNA干扰技术筛选及其他研究，发现了肝细胞生长调节因子酪氨酸激酶蛋白底物（hepatocyte growth factor-regulated tyrosine kinase substrate，HRS）在EV71激活TLR7信号通路中起关键作用。
HRS是一种重要的胞内体（endosome）蛋白，在调控细胞内蛋白的组装和分选中起重要作用。该团队进一步发现EV71能促进HRS表达，且证实HRS与TLR7直接相互作用，促进TLR7复合体在早期胞内体和晚期胞内体中的组装与激活。
HRS interacts with TLR7 and TAB1 in the TLR7 complex during viral infection.
研究结果证明：在感染过程中，EV71上调HRS表达，HRS接下来通过激活TLR7/NF-κB/p38 MAPK信号通路，促进炎症因子表达，导致宿主炎症反应；同时HRS也能通过上调TLR7/NF-κB/IRF3信号通路，诱导干扰素产生，导致抗病毒免疫应答。因此，揭示了EV71感染引起宿主炎症反应和免疫应答的新机制。
A proposed mechanism underlying HRS regulates TLR7-mediated inflammatory and immune responses.
值得注意的是：吴教授团队于曾于2017年1月6日在PLoS Pathogens杂志上发表文章“EV71 3D protein binds with NLRP3 and enhances the assembly of inflammasome complex”（DOI:10.1371/journal.ppat.1006123），报道了EV71的3D蛋白（RNA聚合酶）在病毒感染导致宿主炎症反应中发挥了重要作用，并阐述了EV71感染激活NLRP3炎性小体的新机制。该论文的共同通讯作者为吴建国教授和刘映乐副教授，共同第一作者为王文标博士和肖风博士生。
附文献信息：
Title：HRS plays an important role for TLR7 signaling to orchestrate inflammation and innate immunity upon EV71 infection
DOI:10.1371/journal.ppat.1006585
Abstract：Enterovirus 71 (EV71) is an RNA virus that causes hand-foot-mouth disease (HFMD), and even fatal encephalitis in children. Although EV71 pathogenesis remains largely obscure, host immune responses may play important roles in the development of diseases. Recognition of pathogens mediated by Toll-like receptors (TLRs) induces host immune and inflammatory responses. Intracellular TLRs must traffic from the endoplasmic reticulum (ER) to the endolysosomal network from where they initiate complete signaling, leading to inflammatory response. This study reveals a novel mechanism underlying the regulation of TLR7 signaling during EV71 infection. Initially, we show that multiple cytokines are differentially expressed during viral infection and demonstrate that EV71 infection induces the production of proinflammatory cytokines through regulating TLR7-mediated p38 MAPK, and NF-κB signaling pathways. Further studies reveal that the expression of the endosome-associated protein hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) is upregulated and highly correlated with the expression of TLR7 in EV71 infected patients, mice, and cultured cells. Virus-induced HRS subsequently enhances TLR7 complex formation in early- and late-endosome by interacting with TLR7 and TAB1. Moreover, HRS is involved in the regulation of the TLR7/NF-κB/p38 MAPK and the TLR7/NF-κB/IRF3 signaling pathways to induce proinflammatory cytokines and interferons, respectively, resulting in the orchestration of inflammatory and immune responses to the EV71 infection. Therefore, this study demonstrates that HRS acts as a key component of TLR7 signaling to orchestrate immune and inflammatory responses during EV71 infection, and provides new insights into the mechanisms underlying the regulation of host inflammation and innate immunity during EV71 infection.
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