EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production

• Published in: PLoS pathogens Vol. 15; no. 11; p. e1008142
• Main Authors: Luo, Zhen, Su, Rui, Wang, Wenbiao, Liang, Yicong, Zeng, Xiaofeng, Shereen, Muhammad Adnan, Bashir, Nadia, Zhang, Qi, Zhao, Ling, Wu, Kailang, Liu, Yingle, Wu, Jianguo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.11.2019; Public Library of Science (PLoS)
• Subjects: Animals; Antibodies; Apoptosis; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Astrocytes - virology; Biology and Life Sciences; Body weight; Body weight loss; Brain; Brain - metabolism; Brain - pathology; Brain - virology; Caspase-3; Cell survival; Central nervous system; Cerebral cortex; Child, Preschool; Cleavage; Coxsackievirus infections; Death; Development and progression; Disease; Disruption; Encephalitis; Enterovirus A, Human - isolation & purification; Enterovirus Infections - complications; Enterovirus Infections - virology; Enteroviruses; Epidemics; Female; Foot and mouth disease; Funding; Hand-foot-and-mouth disease; Health aspects; House mouse; Humans; Immune system; Infant; Infants; Infection; Infections; Inflammation; Integrity; Interleukin 6; Interleukin-6 - metabolism; Interleukins; Laboratories; Life sciences; Male; Medicine and Health Sciences; Meningitis; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Microscopy; Neomycin; Nervous system diseases; Neurodegeneration; Neurodegenerative Diseases - epidemiology; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - virology; Neurological diseases; Novels; Pathogenesis; Proteins; Research and Analysis Methods; Rodents; Signaling; Software; Survival; TLR7 protein; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; Toll-like receptors; Virology; Viruses; Weight loss; Japan; China
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008142

As a neurotropic virus, human Enterovirus 71 (EV71) infection causes hand-foot-and-mouth disease (HFMD) and may develop severe neurological disorders in infants. Toll-like receptor 7 (TLR7) acts as an innate immune receptor and is also a death receptor in the central nervous system (CNS). However, the mechanisms underlying the regulation of TLR7-mediated brain pathogenesis upon EV71 infection remain largely elusive. Here we reveal a novel mechanism by which EV71 infects astrocytes in the brain and induces neural pathogenesis via TLR7 and interleukin-6 (IL-6) in C57BL/6 mice and in human astroglioma U251 cells. Upon EV71 infection, wild-type (WT) mice displayed more significant body weight loss, higher clinical scores, and lower survival rates as compared with TLR7-/- mice. In the cerebral cortex of EV71-infected mice, neurofilament integrity was disrupted, and inflammatory cell infiltration and neurodegeneration were induced in WT mice, whereas these were largely absent in TLR7-/- mice. Similarly, IL-6 production, Caspase-3 cleavage, and cell apoptosis were significantly higher in EV71-infected WT mice as compared with TLR7-/- mice. Moreover, EV71 preferentially infected and induced IL-6 in astrocytes of mice brain. In U251 cells, EV71-induced IL-6 production and cell apoptosis were suppressed by shRNA-mediated knockdown of TLR7 (shTLR7). Moreover, in the cerebral cortex of EV71-infected mice, the blockade of IL-6 with anti-IL-6 antibody (IL-6-Ab) restored the body weight loss, attenuated clinical scores, improved survival rates, reduced the disruption of neurofilament integrity, decreased cell apoptotic induction, and lowered levels of Caspase-3 cleavage. Similarly, in EV71-infected U251 cells, IL-6-Ab blocked EV71-induced IL-6 production and cell apoptosis in response to viral infection. Collectively, it's exhibited TLR7 upregulation, IL-6 induction and astrocytic cell apoptosis in EV71-infected human brain. Taken together, we propose that EV71 infects astrocytes of the cerebral cortex in mice and human and triggers TLR7 signaling and IL-6 release, subsequently inducing neural pathogenesis in the brain.