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

PLoS Pathogens

Maolin Ge¹  Qibin Geng²  Ying Xiong²  Zhi Qiao²  Mingfu Tian²  Qi Zhang²  Junbo Chen²  Kailang Wu²  Fang Liu²  Zhen Luo²  Jianguo Wu²  Yingle Liu²  Lan Bai²  Chengliang Zhu² 

[1] Institute of Medical Microbiology, Jinan University, Guangzhou, China;State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China

关键词: Cytokines;    Immune receptor signaling;    Transcription factors;    Macrophages;    Toll-like receptors;    MAPK signaling cascades;    Inflammation;    Enzyme-linked immunoassays;   

DOI  :  10.1371/journal.ppat.1006585

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY