Papel da via de sinalização da Anexina A1 - FPR2 / ALX na patogênese da infecção pelo vírus Chikungunya

Abstract

Introduction: Chikungunya (CHIKV) is an arthritogenic alphavirus that causes a self-limiting disease usually accompanied by joint pain and/or poly-arthralgia with disabling characteristics. Evidence suggests that immune responses mounted during the acute phase of CHIKV infection determine the degree of disease progression and resolution. In addition to the limited available therapeutic interventions, the study of inflammation resolution pathways in the context of CHIKV infection could lead to the generation of new therapeutic interventions. Annexin A1 (AnxA1) is a soluble protein involved in inflammation resolution that regulates functions of a variety of immune cells by binding to formyl peptide receptor 2 (FPR2/ALX). In this study we evaluated the potential of the AnxA1 as a therapeutic target for CHIKV infection. Objective: To evaluate the role of AnxA1 and FPR2 during CHIKV infection in mice. Methods: AnxA1, Fpr2/3 knockout (KO) or wild-type (WT) mice were infected with CHIKV 106 PFU through footpad injections and treated prophylactically or therapeutically with AnxA1 mimetic peptide (Ac2-26, 150µg / animal, i.p). The level of inflammatory mediators, accumulation of immune cells in the paw or in the popliteal lymph node (pLN), the viral titer, the histopathological damage in the paw, as well as the parameters of mechanical hypernociception and paw edema were evaluated. Results: AnxA1 KO mice showed uncontrolled inflammation with increased levels of MPO, CXCL1 and IL-6 and greater accumulation of CD11b+Ly6G+ cells in the paw on the 2nd day post-infection (dpi) and increased accumulation of type 1 conventional dendritic cells (cDCs1) and CD8+ T cells in the paw 7 dpi when compared to WT animals. AnxA1 deficiency increased viral clearance in the organs of mice, aggravated tissue damage in the paw, but did not change the phenotype of virus-induced hypernociception and paw edema. Fpr2/3 KO mice exhibited a disease phenotype similar to the one found in AnxA1 KO mice with increased levels of MPO in the footpad, greater viral clearance in some organs and exacerbated tissue damage in the paw when compared to WT animals. Interestingly, mechanical hypernociception was more prolonged under AnxA1 receptor deficiency. Treatment of WT-infected mice with Ac2-26 decreased inflammation by controlling the levels of MPO, CXCL1 and IL-6 in the footpad. Furthermore, Ac2-26 decreased the accumulation of CD11b+Ly6G+ cells in the paw and reduced the percentage of CD4+ T cells in the pLN of mice infected with CHIKV 2 dpi, reducing the peak of paw edema and decreasing the mechanical hypernociception observed during the infection. Conclusion: Taken together, these findings indicate the relevant role of AnxA1 pathway in CHIKV infection and proposes the AnxA1-FPR2/ALX pathway as a possible therapeutic strategy to control virus-induced acute inflammation induced by CHIKV infection.