The role of activation and metabolic imbalance of dendritic cells for Chikungunya virus pathogenesis

Abstract

The Chikungunya virus (CHIKV) is an emerging arbovirus present in tropical and subtropical regions transmitted by the arthropod vector A. aegypti. Although CHIKV infection may be asymptomatic, it usually leads to the development of an acute febrile illness, joint pain and swelling. One of the major complications associated with CHIKV are chronic manifestations such as arthralgia and arthritis, these symptoms can last for months to years. The chronic disease resulting from CHIKV infection has similar characteristics to rheumatoid arthritis which there is an imbalance in the function of dendritic cells (DCs). Thus, we believe that the infection, activation and metabolic imbalance of dendritic cells may play an essential role in the pathogenesis of CHIKV and in the development of chronic inflammation in the joints. To analyze the effect of CHIKV on the function and metabolism of DCs in vitro, DCs isolated from buffy coat will be infected to characterize viral replication, glycolytic and mitochondrial metabolism, cytokine profile and expression of genes associated with the immune innate response. In addition, different DC subtypes at different time points of the disease, DCs will be used, isolated from patients naturally infected with CHIKV. Finally, we will analyze the replication of CHIKV in different subtypes of DCs isolated from deficient mice of components of the innate immune response (Ifnar-/-, Mavs-/-) and key metabolic sensors (CD11ccreHIF-1±fl/fl, CD11ccre/AMPKfl/fl, CD11ccre/Raptorfl/fl (MTORC1 KO) and CD11ccre/Rictorfl/fl) and we will determine the susceptibility and viral tropism in WT, CD11c-DTR e CD11ccreHIF-1±fl/fl mice. Thus, it will be possible to determine the role of activation and immunometabolism of different DCs in the control and development of the different clinical manifestations by CHIKV.