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

English version

Autoři: Zhen Luo ^aff001; Rui Su ^aff002; Wenbiao Wang ^aff001; Yicong Liang ^aff001; Xiaofeng Zeng ^aff003; Muhammad Adnan Shereen ^aff002; Nadia Bashir ^aff002; Qi Zhang ^aff002; Ling Zhao ^aff004; Kailang Wu ^aff002; Yingle Liu ^aff001; Jianguo Wu ^aff001
Působiště autorů: Guangdong Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China ^aff001; State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China ^aff002; School of Forensic Medicine, Kunming Medical University, Kunming, China ^aff003; State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China ^aff004
Vyšlo v časopise: EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008142
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008142

Souhrn

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.

Klíčová slova:

Apoptosis – Astrocytes – Cerebellum – Cerebral cortex – Immunohistochemistry techniques – Mouse models – Neurons – Toll-like receptors

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