ABSTRACT
Background: The aim of this study was to identify the cause of lymphopenia, strongly predictive of survival in COVID-19. Methods: We recruited PCR-positive SARS-CoV-2-infected patients upon admission to Intensive Care Units (ICU, n = 29) and to the Infectious Diseases Department (non-ICU, n = 29) at Nîmes University Hospital, as well as age-and sex-matched healthy controls (HC). Their Angiotensin II plasma levels were measured by ELISA and their monocytic reactive oxygen species (ROS) production and T-cell apoptosis were measured by flow cytometry using dichloro-dihydro-fluorescein diacetate and fluorescent annexin V, respectively. DNA damage and double strand breaks were quantified in immunofluorescence using antibodies specific for-γ-H2AX and 53BP1, respectively. Results: The monocytes of certain COVID-19 patients spontaneously released ROS able to induce DNA damage and apoptosis in neighboring cells. High ROS production was predictive of death. Indeed, in most patients we observed the presence of DNA damage in up to 50% of their peripheral mononuclear blood cells, with double-strand DNA breaks, and T-cell apoptosis. The intensity of this DNA damage was linked to lymphopenia. SARS-CoV-2 is known to induce the internalization of its receptor, Angiotensin Converting Enzyme 2, a protease able to catabolize Angiotensin II. Accordingly, we observed high plasma levels of Angiotensin II in ROS-producing patients. In search of the stimulus responsible for their ability to release ROS, we unveiled that Angiotensin II triggers ROS production by monocytes via Angiotensin receptor I (AT1). ROS released by Angiotensin II-activated monocytes induced DNA damage and apoptosis in neighboring cells. Conclusion: Mononuclear cell apoptosis provoked via DNA damage due to the release of monocytic ROS could play a major role in COVID-19 pathogenesis, inasmuch as ROS are also known to trigger inflammatory cytokine production. Unveiling this new pathogenic pathway opens up new therapeutic possibilities for COVID-19 based on the early association of AT1 antagonists and antioxidants.