Human microbiome-derived peptide affects the development of experimental autoimmune encephalomyelitis via molecular mimicry
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Background
Gut commensal microbiota has been identified as a potential environmental risk factor for multiple sclerosis (MS), and numerous studies have linked the commensal microorganism with the onset of MS. However, little is known about the mechanisms underlying the gut microbiome and host-immune system interaction.
Results
Here, we introduce the concept of molecular mimicry to address this issue by mining human microbial-derived peptides based on their similarity to the MHC II-TCR binding pattern of self-antigens. We analyzed 304,246 human microbiome genomes and 103 metagenomes collected from the MS cohort and identified 731 nonredundant analogs of myelin oligodendrocyte glycoprotein peptide 35-55 (MOG 35-55 ). Of note, half of these analogs could bind to MHC II and interact with TCR through structural modeling of the interaction using fine-tuned AlphaFold. Among the 8 selected peptides, the peptide (P3) derived from human gut commensal Akkermansia muciniphila shows the ability to activate MOG 35-55 -specific CD4 + T cells in vitro and exacerbate the development of experimental autoimmune encephalomyelitis (EAE) in mice. Furthermore, dendritic cells could process and present P3 to MOG-specific CD4 + T cells and activate these cells. Collectively, our data suggests the potential involvement of a MOG 35-55 -mimic peptide derived from the gut microbiota as a molecular trigger of EAE pathogenesis.
Conclusions
Our findings offer direct evidence of how microbes can initiate the development of EAE, suggesting a potential microbiome-based therapeutic target for inhibiting the progression of MS.
