Dissecting the complexity of heart infiltrates in post-infectious myocarditis induced with CVB3 infection by single-cell RNA sequencing analysis

Abstract

Abstract Viral myocarditis is a predominant cause of heart failure in children and young adolescents that can lead to dilated cardiomyopathy (DCM). Experimentally, Coxsackievirus B3 (CVB) is commonly employed to study the pathogenesis of myocarditis. Post-infectiously, affected mice can develop DCM, and viral RNA may be present with or without inflammation raising a question as to the events culminating in the development of DCM. To dissect this complexity, we sought to characterize heart infiltrates from CVB infected mice by single-cell RNA sequencing and compared the profiles with healthy mice. These analyses revealed 26 subtypes of cells with fibroblasts, T cells and macrophages as the major constituents. Other cell types include endothelial cells (EC), smooth muscle cells, granulocytes, B cells, and innate lymphoid cells. By analyzing the transcriptomes, we noted differential expression of transcription factors (TFs) in various cell types. One such cell type is EC, in which, activating transcription factor 4, interferon regulatory factor 1 (IRF1) and signal transducer and activator of transcription 6 (STAT6) that have a role in apoptosis and inflammation were upregulated. Correspondingly, expression of Myc and nuclear factor erythroid-derived 2-like 2 implicated in EC survival and angiogenesis was downregulated. The data suggests the ECs may play a role in the pathogenesis of CVB infection through a proinflammatory transcriptional program.