Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection in mice.

Cellular and molecular mechanisms driving morbidity following SARS-CoV-2 infection have not been well defined. The receptor for advanced glycation end products (RAGE) is a central mediator of tissue injury and contributes to SARS-CoV-2 disease pathogenesis. In this study, we temporally delineated key cell and molecular events leading to lung injury in mice following SARS-CoV-2 infection and assessed efficacy of therapeutically targeting RAGE to improve survival. Early following infection, SARS-CoV-2 replicated to high titers within the lungs and evaded triggering inflammation and cell death. However, a significant necrotic cell death event in CD45- populations, corresponding with peak viral loads, was observed on day 2 after infection. Metabolic reprogramming and inflammation were initiated following this cell death event and corresponded with increased lung interstitial pneumonia, perivascular inflammation, and endothelial hyperplasia together with decreased oxygen saturation. Therapeutic treatment with the RAGE antagonist FPS-ZM1 improved survival in infected mice and limited inflammation and associated perivascular pathology. Together, these results provide critical characterization of disease pathogenesis in the mouse model and implicate a role for RAGE signaling as a therapeutic target to improve outcomes following SARS-CoV-2 infection.

Targeting RAGE to prevent SARS-CoV-2-mediated multiple organ failure: Hypotheses and perspectives.

A novel infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in December 2019 and declared as a global pandemic by the World Health. Approximately 15% of patients with COVID-19 progress to severe pneumonia and eventually develop acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure with high morbidity and mortality. Evidence points towards a determinant pathogenic role of members of the renin-angiotensin system (RAS) in mediating the susceptibility, infection, inflammatory response and parenchymal injury in lungs and other organs of COVID-19 patients. The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily, has important roles in pulmonary pathological states, including fibrosis, pneumonia and ARDS. RAGE overexpression/hyperactivation is essential to the deleterious effects of RAS in several pathological processes, including hypertension, chronic kidney and cardiovascular diseases, and diabetes, all of which are major comorbidities of SARS-CoV-2 infection. We propose RAGE as an additional molecular target in COVID-19 patients for ameliorating the multi-organ pathology induced by the virus and improving survival, also in the perspective of future infections by other coronaviruses.