Cytomegalovirus Latency Fuels Inflammation Following Myocardial Infarction

Abstract

BACKGROUND: Epidemiological studies have consistently associated cytomegalovirus (CMV) seropositivity with adverse cardiovascular outcomes. However, the mechanisms by which cytomegalovirus infection impacts pathophysiology in the heart remain poorly understood. In this study, we sought to dissect how latent murine cytomegalovirus infection impacts cardiac immune cell dynamics at steady-state and during postmyocardial infarction (MI) repair. METHODS: Experimental MI studies were conducted in C57BL/6J mice previously infected with murine cytomegalovirus. In situ inflammatory responses were characterized by spectral flow cytometry, bulk and single-cell RNA/T-cell receptor (TCR) sequencing, whereas cardiac function was monitored by echocardiography and cardiac magnetic resonance imaging. Moreover, we retrospectively assessed the cytomegalovirus serostatus and associated T-cell expansions in a well-characterized patient cohort with longitudinal cardiac magnetic resonance imaging data available and performed bulk TCR sequencing on peripheral blood and myocardial samples to identify cytomegalovirus-specific TCRs. RESULTS: Our findings show that exposure to murine cytomegalovirus induces long-term changes in the cardiac transcriptional profile and alterations in various cardiac-resident immune cell populations, including the establishment of virus-specific memory CD8 + T-cell residency. Compared with infarcted controls, mice previously exposed to murine cytomegalovirus exhibited stronger inflammatory responses marked by increased CD8 + T-cell infiltration and worsened cardiac function following MI. These observations in mice were supported by data from patients with cytomegalovirus seropositive MI, who harbored cytomegalovirus-responsive T cells in the heart. CONCLUSIONS: Our findings demonstrate that latent cytomegalovirus infection leads to long-term changes in the cardiac microenvironment, which ultimately impair post-MI healing outcomes.