Atherosclerosis licenses for an exceeding immune response in COVID-19 disease by interferon priming in circulating myeloid cells

Patients with cardiovascular disease (CVD) have an increased risk of developing severe respiratory infections, including COVID-19. However, the underlying molecular mechanisms are not completely understood. It has been previously shown that CVD predisposes to an altered responsiveness to subsequent inflammatory triggers by an imprinted epigenetic memory in innate immune cells. Therefore, we hypothesized that patients with pre-existing atherosclerotic cardiovascular disease (ASCVD) and COVID-19 display a dysregulated inflammatory response compared to patients without ASCVD due to epigenetically altered immune cells leading to increased disease severity.

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 expression of inflammatory mediators 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 ASCVD display an exaggerated inflammatory response during moderate COVID-19.

This study demonstrates that patients with ASCVD show a dysregulated myeloid immune response in moderate COVID-19 disease. Mechanistically, epigenetic imprinting sensitizes myeloid cells of patients with ASCVD to an exaggerated type I interferon-associated immune response.