Inflammatory cardiomyopathy is a disease arising from targeting of autoreactive T-cells to a patient’s cardiac muscle. Specifically autoreactive T-cells are generated against Myosin Heavy Chain 6 (MYH6), a crucial component of cardiac muscle. Treatments for this condition remain elusive, as the underlying mechanism of autoreactive T-cell generation has not been well understood. Using a mouse model of progressive inflammatory cardiomyopathy, the authors of this paper were able to show that MYH6-like protein epitopes, generated by bacteria of the gut could lead to generation of autoreactive T-cells and increased mortality. Using in silico modeling, the authors were also able to identify a species specific β-galactosidase gene from the bacterium Bacteroides thetaiotaomicron (B. theta), that was predicted to condition autoreactive T-cells against MYH6. Using germ-free mice inoculated with B. thetalacking this gene, the authors were able to confirm that B. thetaexpressing β-galactosidase contributes to the progression of inflammatory cardiomyopathy. The results of these findings in mice were recapitulated in serum samples of human patients with inflammatory cardiomyopathy, which revealed elevated levels of antibodies targeting B. thetaβ-galactosidase. Finally the authors showed significant improvements in mouse survival rates when antibiotics were administered to reduce the level of gut bacteria and prevent generation of autoreactive T-cells. This work demonstrates a clearer mechanism of the development of inflammatory cardiomyopathy as well as demonstrating possible treatments to reduce the progression of the disease.
By: Nate Dempsey
DOI: 10.1126/science.aav3487