HRS plays an important role for TLR7 signaling to orchestrate inflammation and innate immunity upon EV71 infection

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.

肠道病毒71型（Enterovirus 71, EV71）是一种RNA病毒，可引发儿童手足口病（hand-foot-mouth disease, HFMD），甚至致死性脑炎。尽管EV71的致病机制目前仍未完全阐明，但宿主免疫应答可能在疾病发生发展过程中发挥重要作用。Toll样受体（Toll-like receptors, TLRs）介导的病原体识别可触发宿主免疫与炎症应答，而胞内TLRs需从内质网（endoplasmic reticulum, ER）转运至内溶酶体网络，在此处启动完整的信号通路，进而引发炎症应答。本研究揭示了EV71感染过程中TLR7信号通路调控的全新机制。首先，本研究证实病毒感染过程中多种细胞因子呈差异表达，并证明EV71感染通过调控TLR7介导的p38丝裂原活化蛋白激酶（p38 MAPK）与核因子κB（NF-κB）信号通路，诱导促炎细胞因子的产生。进一步研究发现，在EV71感染的患者、小鼠及培养细胞中，内体相关蛋白肝细胞生长因子调节的酪氨酸激酶底物（hepatocyte growth factor-regulated tyrosine kinase substrate, HRS）的表达水平显著上调，且与TLR7的表达高度相关。病毒诱导产生的HRS可通过与TLR7及TAB1结合，促进早期内体与晚期内体中TLR7复合物的形成。此外，HRS可分别通过调控TLR7/NF-κB/p38 MAPK与TLR7/NF-κB/干扰素调节因子3（IRF3）信号通路，诱导促炎细胞因子与干扰素的产生，从而协同调控EV71感染过程中的炎症与免疫应答。综上，本研究证实HRS作为TLR7信号通路的关键组分，在EV71感染过程中协同调控免疫与炎症应答，并为阐明EV71感染过程中宿主炎症与固有免疫的调控机制提供了新的视角。