Human cardiomyocytes with trisomy 21 exhibit heightened susceptibility and immunological response to SARS-CoV-2 infection

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is associated with significant cardiovascular complications, including myocardial injury and long-term cardiac dysfunction. Individuals with Down syndrome (trisomy 21) exhibit increased susceptibility to severe COVID-19 outcomes, yet the cardiomyocyte-intrinsic mechanisms underlying this vulnerability remain poorly understood. To investigate genotype-specific responses to SARS-CoV-2 infection, we generated induced pluripotent stem cell-derived cardiomyocytes from individuals with trisomy 21 and their euploid, sex-matched biological relatives. Cardiomyocytes were inoculated with SARS-CoV-2, and viral susceptibility was assessed by immunofluorescence. Bulk RNA sequencing was performed under baseline and infected conditions to define transcriptional programs associated with viral response. Trisomy 21 iPSC-CMs exhibited increased susceptibility to SARS-CoV-2 infection, with greater viral protein expression and a higher proportion of infected cardiomyocytes compared to controls. Baseline transcriptomic analysis revealed no significant differences in canonical viral entry factors including ACE2 and TMPRSS2, suggesting that differential susceptibility is not driven by entry receptor availability. Following infection, both trisomy 21 and euploid control groups activated conserved antiviral pathways; however, trisomy 21 cardiomyocytes displayed a markedly amplified transcriptional response, with substantially greater numbers of differentially expressed genes. Upregulated pathways included interferon signaling, NF-{kappa}B activation, cytokine and chemokine signaling, and innate immune responses, while downregulated pathways were enriched for cardiomyocyte structural integrity, calcium handling, and metabolic processes. Notably, inflammatory and cytokine-related transcripts were significantly more elevated in trisomy 21 cells, consistent with an exaggerated immune response. These findings provide mechanistic insight into the increased cardiovascular risk observed in individuals with Down syndrome and highlight dysregulated immune signaling as a potential therapeutic target in this high-risk population.