Human microbiome-derived peptide affects the development of experimental autoimmune encephalomyelitis via molecular
Xin Ma1, Jian Zhang2, Qianling Jiang1
1Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
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.
Methods:
We employed bioinformatics methodologies to identify human microbial-derived peptides by analyzing their similarity to the MHC II-TCR binding patterns of self-antigens. Subsequently, we conducted a range of in vitro and in vivo assays to assess the encephalitogenic potential of these microbial-derived peptides.
Findings:
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 (MOG35-55). 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) shows the ability to activate MOG35-55-specific CD4+ T cells in vitro. Furthermore, P3 shows encephalitogenic capacity and has the potential to induce EAE in some animals. Notably, mice immunized with a combination of P3 and MOG35-55 develop severe EAE. Additionally, dendritic cells could process and present P3 to MOG35-55-specific CD4+ T cells and activate these cells.
Interpretation:
Our data suggests the potential involvement of a MOG35-55-mimic peptide derived from the gut microbiota as a molecular trigger of EAE pathogenesis. Our findings offer direct evidence of how microbes can initiate the development of EAE, suggesting a potential explanation for the correlation between certain gut microorganisms and MS prevalence.
Funding:
National Natural Science Foundation of China (82371350 to GY).
Insights
Gut microbes may trigger multiple sclerosis (MS) by producing peptides that mimic the body's own proteins. This study identified a microbial peptide that can initiate an autoimmune response similar to experimental autoimmune encephalomyelitis (EAE), a model for MS.
Area of Science:
- Immunology
- Microbiology
- Neuroscience
Background:
- The gut microbiome is implicated as an environmental risk factor in multiple sclerosis (MS).
- Mechanisms linking gut microbiota and host immune system interactions in MS remain poorly understood.
Purpose of the Study:
- To investigate the role of gut microbial peptides in initiating autoimmune responses relevant to MS.
- To identify specific microbial-derived peptides that mimic self-antigens and trigger T cell activation.
Main Methods:
- Bioinformatics analysis of human microbiome genomes to identify microbial peptides resembling self-antigens.
- In vitro and in vivo assays to evaluate the encephalitogenic potential of identified peptides.
- Structural modeling using AlphaFold to predict peptide-MHC II-TCR interactions.
Main Results:
- Identified 731 analogs of myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) from human microbiome data.
- A specific microbial peptide (P3) was found to activate MOG35-55-specific CD4+ T cells and induce experimental autoimmune encephalomyelitis (EAE) in mice.
- Dendritic cells processed and presented P3, activating autoreactive T cells, highlighting a potential molecular mimicry mechanism.
Conclusions:
- Gut microbiota-derived peptides mimicking MOG35-55 may act as molecular triggers for EAE pathogenesis.
- These findings provide direct evidence for microbial initiation of EAE, explaining the link between gut microbes and MS prevalence.
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