Bioinformatics Analysis of Gut Microbiota and CNS Transcriptome in Virus-Induced Acute Myelitis and Chronic Inflammatory Demyelination; Potential Association of Distinct Bacteria With CNS IgA Upregulation
Bioinformatics Analysis of Gut Microbiota and CNS Transcriptome in Virus-Induced Acute Myelitis and Chronic Inflammatory Demyelination; Potential Association of Distinct Bacteria With CNS IgA Upregulation
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DOI：
10.3389/fimmu.2020.01138
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发表时间：
2020-07
影响因子：
7.3
通讯作者：
S. Omura;F. Sato;A. Park;M. Fujita;S. Khadka;Yumina Nakamura;Aoshi Katsuki;K. Nishio;F. Gavins;Ikuo Tsunoda
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文献类型：
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作者：
S. Omura;F. Sato;A. Park;M. Fujita;S. Khadka;Yumina Nakamura;Aoshi Katsuki;K. Nishio;F. Gavins;Ikuo Tsunoda
病毒感染与急性和慢性炎性中枢神经系统（CNS）疾病相关，例如，急性弛缓性肌病（AFM）和多发性硬化（MS），其中动物模型支持病毒的致病作用。在脊髓中，Theiler鼠脑脊髓炎病毒（TMEV）在急性期、感染后1周（p.i.）以及在慢性期期间具有白色炎症的MS样疾病，1个月p.i.虽然肠道微生物群已被提出影响免疫反应，导致远端器官的病理状况，包括脑病理生理学，但其在神经炎性疾病中的确切作用尚不清楚。我们用TMEV感染SJL/J小鼠，在感染后第4天（发病前）、第7天（急性期）和第35天（慢性期）收集粪便和脊髓;并通过16 S rRNA测序检查粪便微生物群，通过RNA测序检查CNS转录组。虽然TMEV感染既没有降低微生物多样性，也没有改变整体微生物组模式，但它在感染后第7天和第35天增加了单个细菌属Marvinbryantia的丰度。感染后第35天感染粪球菌，其与CNS转录组的模式匹配显示出强相关性：Marvinbryantia在感染后第7天具有8个T细胞受体（TCR）基因，在感染后第35天具有7个免疫球蛋白（IG）基因;粪球菌不仅表达TCR和IgG/伊加，而且还表达主要组织相容性复合体（MHC）和补体。伊加的高基因表达，粘膜免疫的一个组成部分，在中枢神经系统中是出乎意料的。然而，我们观察到大量的伊加阳性细胞和沉积在中枢神经系统，以及中枢神经系统伊加基因表达和血清抗TMEV伊加滴度之间的强相关性。在这里，少数不同肠道细菌的变化，而不是整体肠道微生物群的变化，可能会影响急性和慢性免疫反应，导致CNS中的AFM和MS样病变。或者，激活的免疫反应会改变肠道微生物群的组成。
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.