AVE0991, a Mas receptor agonist, increases influenza and COVID-19 severity in vivo

Dysregulation of the renin-angiotensin system (RAS) contributes to severe influenza and COVID-19, potentially via impaired ACE2/Ang-(1-7)/Mas receptor (MasR) signalling. AVE0991, an orally bioavailable MasR agonist, protects against non-infectious lung inflammation, but its effects in viral respiratory disease are unknown. We evaluated AVE0991 in human lung epithelial cells and murine models of influenza A virus (IAV) and SARS-CoV-2 infection. In vitro , AVE0991 suppressed cytokines IL-6 and TNF-α to both IAV and SARS-CoV-2 and reduced IAV titres. Unexpectedly, in vivo treatment worsened disease. These findings highlight discordant in vitro and in vivo effects and underscore the need for careful evaluation of RAS-targeted therapies in acute viral infection.