Single cell RNA sequence analysis reveals novel clusters unique to post-infectious myocarditis in the mouse model of Coxsackievirus infection

Abstract

Abstract Myocarditis is a common occurrence in children and adolescents that can lead to dilated cardiomyopathy. Since it is difficult to identify the triggers of this complex disease, mechanistic understanding of DCM pathogenesis may create avenues to develop new treatment strategies. We have been engaged in delineating the autoimmune pathways underlying the development of DCM using various mouse models of myocarditis that resemble human disease. One such model is Coxsackievirus B3 (CVB)-induced myocarditis in A/J mice that show two distinct phases of disease, but occur in continuum. While, the acute, infectious phase (up to ~10 days post-infection) is marked by viremia and infiltrations in the hearts, infectious virions become undetected during the chronic phase (~beyond 18 days post-infection), and animals develop DCM. The latter phenotype can occur over a period of ~60 to 90 days, and hitherto, it has been a challenge to determine the underlying mechanisms. To dissect this complex nature of disease, we recently performed single cell RNA sequence analysis on heart infiltrates obtained from CVB-infected mice. Using panels of 15 to 30 marker genes for various immune and non-immune cells, we identified 18 and 26 clusters respectively in healthy and infected hearts that also include few unknown clusters unique for each group. Likewise, transcriptome analyses led us to identify a total of 14,051 genes to be differentially expressed, and of these, 206 and 345 transcripts were unique to healthy and CVB-infected groups, respectively. The data suggest that uniquely expressed genes in the CVB-infected hearts may have a role in the development of post-infectious myocarditis leading to DCM.