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.

Highlights

  • Upon infection, viral RNAs are recognized as pathogen-associated molecular patterns (PAMPs) by Toll-like receptors (TLRs) to trigger signaling events leading to the induction of interferons (IFNs) and proinflammatory cytokines [1, 2]

  • The production of colony stimulating factor 3 (CSF3), IL-1β, and IL-6 was evaluated in Enterovirus 71 (EV71)-infected human acute monocytic leukemia cells (THP-1), differentiated macrophages derived from THP-1 cells [23] (S1D Fig), and human peripheral blood mononuclear cells (PBMCs) cells

  • Enzyme-linked immunosorbent assay (ELISA) analyses revealed that CSF3, IL-1β, and IL-6 proteins were induced by EV71 or R848 as a stimulus control [24], but not by mock-infection or UVinactivated EV71, in THP-1, macrophages, and human PBMCs (Fig 1D–1F)

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Summary

Introduction

Viral RNAs are recognized as pathogen-associated molecular patterns (PAMPs) by Toll-like receptors (TLRs) to trigger signaling events leading to the induction of interferons (IFNs) and proinflammatory cytokines [1, 2]. Hepatitis C virus, and vesicular stomatitis virus) activate TLR7, which is initiated by binding of TLR7 to the myeloid differentiation factor 88 (MyD88) adapter protein and interleukin-1 receptor-associated kinases (IRAK) and by recruiting tumor necrosis factor receptor-associated factor 6 (TRAF6), transforming growth factor 1-activated kinase-1 (TAK1) and TAK1-binding protein 1/2 (TAB1/2) [6, 7] These events subsequently activate multiple signaling cascades, mitogen-activated protein kinase (MAPK), nuclear transcription factor-κB (NF-κB) and IFN regulatory factor 3/7 (IRF3/7), to induce the production of proinflammatory cytokines and IFNs, resulting in antiviral response and innate immunity [3, 8]. The molecular mechanism by which EV71 infection induces TLRs-mediated inflammatory responses is still largely unknown

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