Murine cytomegalovirus infection triggers onset of arrhythmogenic cardiomyopathy in Pkp2-deficient mice through a macrophage-driven immune response

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Abstract Background Arrhythmogenic cardiomyopathy (ACM) is a genetically-driven disorder with a broad spectrum of cardiac manifestations, ranging from asymptomatic cases to severe heart failure. ACM is often associated with genetic variations in desmosomal proteins, particularly plakophilin 2 (PKP2). Some clinically affected individuals experience 'hot phases' resembling acute myocarditis. The role of external factors, such as viral infections, in ACM onset and progression remains elusive. Therefore, we examined the effects of murine cytomegalovirus (MCMV) infection on ACM using mice with heterozygous cardiomyocyte-specific Pkp2 deficiency (Pkp2+/-), which exhibited no baseline differences compared to wild type (Ctr) mice. Methods and Results Pkp2+/- and Ctr mice were infected with MCMV or PBS to assess cardiac structure, function and immune response at various time points post-infection. Acute infection (5-14 days) induced immune cell aggregates in myocardial tissues, comprising cytotoxic CD8+ and CD4+ T cells, irrespective of genotype. Although viral DNA load diminished over time, it persisted up to 6 months post-infection (6mpi). Our hypothesis proposing inflammation-mediated myocardial damage was supported as systolic dysfunction occurred at 3mpi, progressively worsening in Pkp2+/- MCMV, but not in Ctr MCMV hearts. Notably, fibrosis was absent in cardiac tissue, but immune cell infiltration predominated. Besides the anticipated CD8+ T-cell accumulation, we observed significantly increased monocytes/macrophages, exclusively in Pkp2+/- MCMV mice. Single-cell RNA seq revealed distinct immune cell sub-clusters, including Ly6Chi monocytes and pro-fibrotic macrophages, particularly in Pkp2+/- MCMV mice. These populations were also present in Pkp2+/- hearts without infection, indexing a subclinical effect of the Pkp2 mutation and involvement of macrophages in the early disease response. Importantly, cytokine analyses from heart lysates and serum samples indicated an upregulation of pro-inflammatory cytokines and chemokines (e.g. IL-1ß, CCL2) in a genotype-dependent manner. Further immune cell analyses in homozygous Pkp2 knockout (Pkp2-/-) mice, exhibiting pronounced immune cell infiltrations at an early stage, demonstrated a shift from tissue-resident (TIM4+ MHCII-) to pro-inflammatory (TIM4- MHCII+) and tissue-injury-associated macrophages (TIM4- MHCII-), suggesting activated states and mediator secretion exacerbating tissue damage as crucial factors in ACM. Conclusion The heterogeneous clinical presentations of ACM may result from the interplay between genetic susceptibility and immune responses. Our study highlights that compromised desmosomes, combined with an inflammatory trigger like MCMV infection, can initiate cardiac dysfunction, likely through exaggerated immune activation and progressive tissue damage. Furthermore, specific targeting of migrating monocytes might modulate the pro-inflammatory response, potentially slowing ACM development.

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