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Cytomegalovirus latency exacerbates cardiac inflammation and tissue remodeling after myocardial infarction

ABSTRACT: Background: Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide, with immune-mediated processes increasingly recognized as important contributors to CVD onset and progression. Seropositivity rates indicate 60–90% of the population carries latent viral infections, e.g., with cytomegalovirus, that profoundly shape the individual immune phenotype. Epidemiological studies have consistently associated cytomegalovirus (CMV) seropositivity with adverse cardiovascular outcomes, yet the functional consequences of latent CVM cytomegalovirus latency in the context of myocardial infarction (MI) have not been studied, nor has its underlying influence on cardiac tissue. Methods: In this study we employed a murine model of cytomegalovirus (MCMV) infection to investigate the impact of the virus in the cardiac immune environment. We characterized the immune cell populations involved in cardiac immune responses by flow cytometry and performed bulk RNA seq of infected and naive mice to dissect the transcriptional differences that occur after viral exposure. To better understand how viral infections affect the myocardium of infected and naive animals post MI, we conducted a series of experiments involving flow cytometry, single-cell RNA / TCR sequencing, echocardiography, and cMRI 5 days after mice underwent experimental MI. Additionally, we used cMRI to stratify CMV- seropositive patients as “good” or “poor healers” and tested their CMV IgG titers. Using TCR-sequencing, we also identified CMV-responding TCRs and compared blood-derived and heart-derived T cells from post-mortem tissues. Results: Our findings show that exposure to murine CMV induces both long-term changes in the cardiac transcriptional profile and alterations in cardiac immune cell populations. We detected the establishment of virus-specific resident memory T cells that persist in cardiac tissue. Following myocardial infarction (MI), mice previously exposed to MCMV had more abundant cardiac-resident T cells, heightened inflammatory profile, and adverse ventricular remodeling, as revealed by MRI, compared to naive controls. These murine observations were supported by data from CMV-seropositive MI patients, who harbored CMV-responsive T cells and exhibited impaired cardiac healing. Conclusions: Taken together, our findings demonstrate that latent CMV infection leads to long-term immunological changes in cardiac tissue that exert significant effects on post-MI healing outcome.

ORGANISM(S): Mus musculus

PROVIDER: GSE309570 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:Reconstitution of cytomegalovirus (CMV)-specific immunity following transplant remains a primary clinical objective to prevent CMV disease, and adoptive immunotherapy of CMV-specific T cells can be an effective therapeutic approach. Due to the persistence of CMV, most CMV-specific CD8+ T cells become terminally differentiated effector cells (TEFF). However, a minor subset retains a memory phenotype (TM). Interestingly, recent studies suggest that CMV-specific CD8+ T cells with different phenotypes may have different abilities to reconstitute sustained immunity following transfer. The immunology of human CMV (HCMV) infections is reflected in the mouse model of MCMV infection. We found that HCMV- and MCMV-specific T cells displayed shared genetic programs, validating the MCMV model for studies of CMV-specific T cells in vivo. After transfer, the proliferative capacity of MCMV-specific TM cells was vastly superior to TEFF cells. Strikingly, TM cells expanded and established sustained and diverse T cell populations even after multiple challenges. Although both TEFF and TM cells could protect Rag-/- mice, only TM cells could consistently survive after transfer into immune replete, latently infected recipients and respond if recipient immunity was lost. These data show that CMV-specific TM cells retain memory function during persistent infection and can re-establish CMV immunity when necessary. C57BL/6 mice were infected intraperitoneally (i.p.) with MCMV strain MW97.01 between 6-16 weeks of age. Splenocytes were isolated from chronically-infected mice and co-stained with three PE-conjugated tetramers loaded with the antigenic peptides from M38, m139 and IE3, all of which promote memory inflation. Cells were then stained with fluorescently conjugated antibodies and sorted on a MoFlo cell sorter. Naïve CD8+ cells were identified as CD44lo. MCMV-specific T cells were identified as CD8+, CD44hi and tetramer binding and then further segregated into memory and effector cells subsets by their expression of KLRG1 and CD127.

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Cytomegalovirus latency exacerbates cardiac inflammation and tissue remodeling after myocardial infarction

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