Avaliação do papel do mediador pró-resolutivo Anexina A1 e de seu receptor, FPR2, na infecção por coronavírus

Abstract

Inflammation is a physiological mechanism essential for the body's homeostasis. However, its overactivation is directly related to tissue damage and death associated with various infections, such as COVID-19. The successful termination of the inflammatory response occurs through the resolution phase, during which the pro-inflammatory stimulus is eliminated, and the leukocytes at the site undergo phenotypic changes to restore homeostasis and the normal functions of the tissues. This process actively involves the combined action of several endogenous pro-resolving mediators, such as Annexin A1 (AnxA1). The pro-resolving potential of AnxA1 is mainly mediated through binding to its specific membrane receptor, FPR2. Given the importance of these molecules in controlling excessive inflammation during viral and bacterial infections, our study aimed to evaluate the role of AnxA1 and FPR2 in coronavirus infection. Our results showed that endogenous AnxA1 is essential for controlling inflammation triggered by murine coronavirus, and that the therapeutic use of its mimetic peptide, Ac2-26, is capable of controlling exacerbated lung inflammation and mortality in SARS-CoV-2-infected mice. Since Ac2-26 transduces the effects of AnxA1, we hypothesized that the FPR2 receptor would have the same impact on the disease. However, our study demonstrates that the absence of the FPR2 receptor protects mice from coronavirus infection by reducing viral replication, lung inflammation, and mortality associated with the infection, while positively modulating the number of specific leukocyte populations in the lungs and the expression of antiviral molecules. Interestingly and counterintuitively, these results suggest that both exogenous administration of AnxA1 and inhibition of its receptors may be promising therapeutic targets in the fight against coronavirus infections, highlighting the context-dependent nature of pro- resolving molecules.