Human Microbiome-derived Peptide Affects the Development of Experimental Autoimmune Encephalomyelitis Via Molecular Mimicry

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2024 Dec 26

PMID 39724786

Authors

Xin Ma

Jian Zhang

Qianling Jiang

Yong-Xin Li

Guan Yang

Affiliations

Soon will be listed here.

Abstract

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 (MOG). 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 MOG-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 MOG develop severe EAE. Additionally, dendritic cells could process and present P3 to MOG-specific CD4 T cells and activate these cells.

Interpretation: Our data suggests the potential involvement of a MOG-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).

References

Johanson 2nd D, Goertz J, Marin I, Costello J, Overall C, Gaultier A . Experimental autoimmune encephalomyelitis is associated with changes of the microbiota composition in the gastrointestinal tract. Sci Rep. 2020; 10(1):15183. PMC: 7494894. DOI: 10.1038/s41598-020-72197-y. View

Lourbopoulos A, Deraos G, Matsoukas M, Touloumi O, Giannakopoulou A, Kalbacher H . Cyclic MOG ameliorates clinical and neuropathological features of experimental autoimmune encephalomyelitis. Bioorg Med Chem. 2017; 25(15):4163-4174. DOI: 10.1016/j.bmc.2017.06.005. View

Motmaen A, Dauparas J, Baek M, Abedi M, Baker D, Bradley P . Peptide-binding specificity prediction using fine-tuned protein structure prediction networks. Proc Natl Acad Sci U S A. 2023; 120(9):e2216697120. PMC: 9992841. DOI: 10.1073/pnas.2216697120. View

Pasolli E, Asnicar F, Manara S, Zolfo M, Karcher N, Armanini F . Extensive Unexplored Human Microbiome Diversity Revealed by Over 150,000 Genomes from Metagenomes Spanning Age, Geography, and Lifestyle. Cell. 2019; 176(3):649-662.e20. PMC: 6349461. DOI: 10.1016/j.cell.2019.01.001. View

Marignier R, Hacohen Y, Cobo-Calvo A, Probstel A, Aktas O, Alexopoulos H . Myelin-oligodendrocyte glycoprotein antibody-associated disease. Lancet Neurol. 2021; 20(9):762-772. DOI: 10.1016/S1474-4422(21)00218-0. View

La Gruta N, Gras S, Daley S, Thomas P, Rossjohn J . Understanding the drivers of MHC restriction of T cell receptors. Nat Rev Immunol. 2018; 18(7):467-478. DOI: 10.1038/s41577-018-0007-5. View

Almeida A, Nayfach S, Boland M, Strozzi F, Beracochea M, Shi Z . A unified catalog of 204,938 reference genomes from the human gut microbiome. Nat Biotechnol. 2020; 39(1):105-114. PMC: 7801254. DOI: 10.1038/s41587-020-0603-3. View

Huseby E, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J . A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med. 2001; 194(5):669-76. PMC: 2195947. DOI: 10.1084/jem.194.5.669. View

Kishikawa T, Ogawa K, Motooka D, Hosokawa A, Kinoshita M, Suzuki K . A Metagenome-Wide Association Study of Gut Microbiome in Patients With Multiple Sclerosis Revealed Novel Disease Pathology. Front Cell Infect Microbiol. 2020; 10:585973. PMC: 7759502. DOI: 10.3389/fcimb.2020.585973. View

10.

Harkiolaki M, Holmes S, Svendsen P, Gregersen J, Jensen L, McMahon R . T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity. 2009; 30(3):348-57. DOI: 10.1016/j.immuni.2009.01.009. View

11.

Berer K, Gerdes L, Cekanaviciute E, Jia X, Xiao L, Xia Z . Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci U S A. 2017; 114(40):10719-10724. PMC: 5635914. DOI: 10.1073/pnas.1711233114. View

12.

Chaumeil P, Mussig A, Hugenholtz P, Parks D . GTDB-Tk v2: memory friendly classification with the genome taxonomy database. Bioinformatics. 2022; 38(23):5315-5316. PMC: 9710552. DOI: 10.1093/bioinformatics/btac672. View

13.

von Meijenfeldt F, Arkhipova K, Cambuy D, Coutinho F, Dutilh B . Robust taxonomic classification of uncharted microbial sequences and bins with CAT and BAT. Genome Biol. 2019; 20(1):217. PMC: 6805573. DOI: 10.1186/s13059-019-1817-x. View

14.

Reynisson B, Barra C, Kaabinejadian S, Hildebrand W, Peters B, Nielsen M . Improved Prediction of MHC II Antigen Presentation through Integration and Motif Deconvolution of Mass Spectrometry MHC Eluted Ligand Data. J Proteome Res. 2020; 19(6):2304-2315. DOI: 10.1021/acs.jproteome.9b00874. View

15.

Li D, Liu C, Luo R, Sadakane K, Lam T . MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph. Bioinformatics. 2015; 31(10):1674-6. DOI: 10.1093/bioinformatics/btv033. View

16.

Jangi S, Gandhi R, Cox L, Li N, von Glehn F, Yan R . Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016; 7:12015. PMC: 4931233. DOI: 10.1038/ncomms12015. View

17.

Ochoa-Reparaz J, Mielcarz D, Ditrio L, Burroughs A, Foureau D, Haque-Begum S . Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol. 2009; 183(10):6041-50. DOI: 10.4049/jimmunol.0900747. View

18.

Lee Y, Menezes J, Umesaki Y, Mazmanian S . Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2010; 108 Suppl 1:4615-22. PMC: 3063590. DOI: 10.1073/pnas.1000082107. View

19.

Cani P, Depommier C, Derrien M, Everard A, de Vos W . Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol. 2022; 19(10):625-637. DOI: 10.1038/s41575-022-00631-9. View

20.

Marzella D, Parizi F, van Tilborg D, Renaud N, Sybrandi D, Buzatu R . PANDORA: A Fast, Anchor-Restrained Modelling Protocol for Peptide: MHC Complexes. Front Immunol. 2022; 13:878762. PMC: 9127323. DOI: 10.3389/fimmu.2022.878762. View