C96-08 Atherosclerosis Impairs Lung Repair and Alveolar Macrophage Function Following Sars-cov-2 Infection in Ldlr -/- Mice

Rationale Cardiovascular diseases (CVDs) and atherosclerosis are among the strongest predictors of poor outcomes in COVID-19, but the cellular mechanisms linking atherosclerosisto impaired recovery remain unclear. Chronic lipid imbalance and vascular inflammation can reshape immune-metabolic responses to viral injury. To explore these processes, we investigated SARS-CoV2-induced pulmonary and cardiac responses in LDLr−/− mice maintained on a fat-rich diet that induces dyslipidemia with systemic atherosclerosis. Methods Atherosclerotic LDLr−/− and wild-type (WT) mice were infected intratracheally with mouse-adapted SARS-CoV2. Viral burden was quantified by qPCR analysis and virus titration. Bronchoalveolar lavage fluid (BALF) protein and LDL activity were measured as indicators of alveolar-capillary barrier integrity. Pulmonary immune cell composition and transcriptional reprogramming were analyzed by flow cytometry and single-cell RNA sequencing (scRNA-seq) until d28 after acute COVID-19. In parallel, immunohistochemistry (IHC) and immunofluorescence (IF) were performed on lung tissue to evaluate potential structural remodeling. Results Although viral RNA levels and survival did not differ between groups, infected LDLr−/− mice exhibited a significant increase in BALF protein and LDL activity, consistent with persistent alveolar-capillary barrier dysfunction. Flow cytometry demonstrated sustained elevation of CD45+ immune cells in BALF, predominantly bone-marrow-derived macrophages (BMDM). scRNA-seq revealed the emergence of a specificalveolar BMDM subset characterized by upregulation of antigen-presentation, lysosomal, and stress-response pathways, together with downregulation of phagocytic, cytoskeletal, and inflammatory modules in lungs of atherosclerotic mice. In addition, tissue resident macrophages displayed stress-adaptive and immunoregulatory signatures rather than homeostatic repair phenotypes. In contrast to WT mice, which restored lung epithelial compartments (AT1, AT2, ciliated, goblet, and bronchioalveolar stem cells [BASCs]) by 28 dpi, LDLr−/− lungs showed persistent depletion of BASCs, goblet, and multiciliated cells. Conclusion High-fat diet-induced dyslipidemia with atherosclerosis in LDLr−/− mice induce specific macrophage reprogramming in COVID-19, maintain immune-cell infiltration, and impair epithelial regeneration independently of viral replication. Transcriptional signatures indicative of sustained lysosomal and stress-response activity suggests dysregulated macrophage phenotypes with prolonged activation and incomplete inflammatory resolution. These findings provide mechanistic insight into the heightened susceptibility of individuals with cardiovascular disease to severe and prolonged COVID-19 lung pathology. This abstract is funded by: DFG, German Research Foundation