Atherosclerosis licenses for an exceeding immune response in COVID-19 disease by interferon priming in circulating myeloid cells
Aims: Patients with cardiovascular disease (CVD) have an increased risk of developing severe respiratory infections, including COVID-19. However, the underlying molecular mechanisms have not been investigated. It has been previously shown that cardiovascular disease predisposes to an altered responsiveness to subsequent inflammatory triggers by an imprinted epigenetic memory in innate immune cells. Therefore, we analysed if patients with preexisting atherosclerotic cardiovascular disease (ASCVD) and COVID-19 display an increased inflammatory response compared to patients without ASCVD due to epigenetically altered immune cells.  Methods and results: Single-cell RNA sequencing revealed a dysregulated myeloid immune response with hyperinflammatory and immunosuppressive features in patients with ASCVD and moderate COVID-19. Assay for Transposase-Accessible Chromatin sequencing and in-vitro experiments with isolated monocytes infected with SARS-CoV-2 showed epigenetic priming of monocytes from patients with ASCVD towards increased inflammation and type I interferon signalling. In a German nationwide cohort (NAPKON), using multiplex cytokine assays, enzyme-linked immunosorbent assays, and bulk-RNA-sequencing, we confirmed that patients with CVD display an increased inflammatory response during moderate COVID-19.  Conclusions: This is the first study to demonstrate that patients with ASCVD show a dysregulated myeloid immune response when infected with SARS-CoV-2. Mechanistically, epigenetic imprinting sensitizes myeloid cells of patients with ASCVD to an exaggerated typ I interferon-associated immune response. Overall design: ATAC-sequencing of PBMC-derived monocytes from individuals with and without atherosclerotic cardiovascular disease (i.e. coronary artery disease)