Abstract
Virus infections have been associated with acute and chronic inflammatory central nervous system (CNS) diseases, e.g., acute flaccid myelitis (AFM) and multiple sclerosis (MS), where animal models support the pathogenic roles of viruses. In the spinal cord, Theiler's murine encephalomyelitis virus (TMEV) induces an AFM-like disease with gray matter inflammation during the acute phase, 1 week post infection (p.i.), and an MS-like disease with white matter inflammation during the chronic phase, 1 month p.i. Although gut microbiota has been proposed to affect immune responses contributing to pathological conditions in remote organs, including the brain pathophysiology, its precise role in neuroinflammatory diseases is unclear. We infected SJL/J mice with TMEV; harvested feces and spinal cords on days 4 (before onset), 7 (acute phase), and 35 (chronic phase) p.i.; and examined fecal microbiota by 16S rRNA sequencing and CNS transcriptome by RNA sequencing. Although TMEV infection neither decreased microbial diversity nor changed overall microbiome patterns, it increased abundance of individual bacterial genera Marvinbryantia on days 7 and 35 p.i. and Coprococcus on day 35 p.i., whose pattern-matching with CNS transcriptome showed strong correlations: Marvinbryantia with eight T-cell receptor (TCR) genes on day 7 and with seven immunoglobulin (Ig) genes on day 35 p.i.; and Coprococcus with gene expressions of not only TCRs and IgG/IgA, but also major histocompatibility complex (MHC) and complements. The high gene expression of IgA, a component of mucosal immunity, in the CNS was unexpected. However, we observed substantial IgA positive cells and deposition in the CNS, as well as a strong correlation between CNS IgA gene expression and serum anti-TMEV IgA titers. Here, changes in a small number of distinct gut bacteria, but not overall gut microbiota, could affect acute and chronic immune responses, causing AFM- and MS-like lesions in the CNS. Alternatively, activated immune responses would alter the composition of gut microbiota.
Highlights
Virus infections can induce tissue damage either by direct virus replication/killing of infected cells or by immune-mediated tissue damage [1, 2]
By comparing and contrasting acute flaccid myelitis (AFM)- and multiple sclerosis (MS)-like diseases induced by a single natural pathogen of mice, Theiler’s murine encephalomyelitis virus (TMEV), we investigated the interactions between altered microbiome and central nervous system (CNS) transcriptome, which would give an insight into the pathophysiology of AFM and MS
During the Acute and Chronic Phases of TMEV has been known to induce a biphasic disease in the CNS: acute polioencephalomyelitis in the gray matter around 1 week p.i. and chronic inflammatory demyelinating disease in the white matter during the chronic phase, around 1 month p.i
Summary
Virus infections can induce tissue damage either by direct virus replication/killing of infected cells (viral pathology) or by immune-mediated tissue damage (immunopathology) [1, 2]. The establishment of mouse models for AFM, using enterovirus D68 (EV-D68), has been reported [5, 9,10,11], the models may not replicate the human disease, because of the usage of neonatal/suckling mice and non-natural pathogen of mice. Viral pathology appears to cause CNS damage in the EV-D68 model, the different susceptibility to the EV-D68 model depending on mouse strains [11] as well as rare isolation of virus from the CSF in human AFM [4, 6] suggested a role of host factors including immunopathology in AFM [12]
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