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EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production.
- Source :
-
PLoS Pathogens . 11/15/2019, Vol. 15 Issue 11, p1-33. 33p. - Publication Year :
- 2019
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Abstract
- 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. Author summary: Enterovirus 71 (EV71) infection causes aseptic meningitis, poliomyelitis-like paralysis and fatal encephalitis in infants. Besides an immune receptor, toll-like receptor 7 (TLR7) serves as a death receptor in central nervous system (CNS). However, the role of TLR7 in EV71-induced neural pathogenesis remains ambiguous. This study reveals a distinct mechanism by which EV71 induces neurodegeneration via TLR7 and interleukin-6 (IL-6). Upon EV71 infection, TLR7-/- mice displayed less body weight loss, lower clinical score, and higher survival rate as compared with wild-type (WT) mice. Meanwhile, a severer histopathologic neurofilaments disruption, neurodegeneration and cell apoptosis were observed in brain of EV71-infected WT mice. IL-6 release, cell apoptosis, and Caspase-3 cleavage were attenuated by shRNA targeting TLR7 (shTLR7) in EV71-infected U251 cells. Moreover, anti-IL-6 antibody (IL-6-Ab) suppressed EV71-induced body weight loss, clinical score increase, and survival rate decrease as well as neurofilaments disruption and neurodegeneration in mice, and it also attenuated EV71-induced cell apoptosis and Caspase-3 cleavage in U251 cells. It's retrospectively observed that TLR7 upregulation, IL-6 induction and astrocytic cell apoptosis in EV71-infected human brain. Therefore, TLR7 is required for neural pathogenesis by IL-6 induction upon EV71 infection. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15537366
- Volume :
- 15
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- PLoS Pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 139685370
- Full Text :
- https://doi.org/10.1371/journal.ppat.1008142