Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy.
Gil-Cruz C., Perez-Shibayama C., De Martin A., Ronchi F., van der Borght K., Niederer R., Onder L., Lütge M., Novkovic M., Nindl V., Ramos G., Arnoldini M., Slack EMC., Boivin-Jahns V., Jahns R., Wyss M., Mooser C., Lambrecht BN., Maeder MT., Rickli H., Flatz L., Eriksson U., Geuking MB., McCoy KD., Ludewig B.
Myocarditis can develop into inflammatory cardiomyopathy through chronic stimulation of myosin heavy chain 6-specific T helper (TH)1 and TH17 cells. However, mechanisms governing the cardiotoxicity programming of heart-specific T cells have remained elusive. Using a mouse model of spontaneous autoimmune myocarditis, we show that progression of myocarditis to lethal heart disease depends on cardiac myosin-specific TH17 cells imprinted in the intestine by a commensal Bacteroides species peptide mimic. Both the successful prevention of lethal disease in mice by antibiotic therapy and the significantly elevated Bacteroides-specific CD4+ T cell and B cell responses observed in human myocarditis patients suggest that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible individuals. The ability to restrain cardiotoxic T cells through manipulation of the microbiome thereby transforms inflammatory cardiomyopathy into a targetable disease.