The aryl hydrocarbon receptor as a potential therapeutic target against dengue virus infection.

DAMONTE, E.B.; TORTI, M.F.; QUINTANA, F.; GIOVANNONI, F.; GARCÍA, C. C.

Congreso; Drug Discovery for Neglected Diseases International Congress 2018; 2018

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that has been classically associated with the mechanism of clearance of xenobiotics. Recently, numerous studies have indicated that AHR has the ability of modulate the immune system. It has been shown that AHR is involved in a negative feedback mechanism with NFκB. Regarding to viral infections, it was shown that the stimulation of AHR reduces the survival of mice infected with influenza A virus as a consequence of the inhibition of the proliferation and differentiation of CD8⁺ T cells andit has also been described the effect of the AHR activation on the interferon signaling pathway. Dengue virus (DENV)belongs to the Flaviviridae family and has four different serotypes (DENV-1,2,3,4) that are capable of causing illness in humans after the bite of infected mosquitoes of the genus Aedes. DENV is considered the most important arthropodborne virus all over the world. The only vaccine that is been developed had shown low effectivity and no specific treatments exists, thus the development of new antiviral strategies is crucial. In the present study we have evaluated the possibility of modulating the activity of AHR to control DENV infection in vitro.In order to achieve this, we used AHR ligand agonists and antagonists to modulate the activity of the receptor to treat A549 cell cultures before the infection with DENV1-4. From the supernatants of the cultures, titrations were carried out to evaluate the viral yields. Also, real-time RT-PCR and indirect immunofluorescence to quantify the viral genomeand protein, respectively, were carried out. The treatment with 20μM of the AHR antagonist CH223191, not only decreased the viral yield in a 95±4%, but also diminished the viral protein expression in an 84,5±0,5%. The preliminary data obtained, allowed us to demonstrate that the AHR signaling pathway is involved in the DENV replication process in vitro, and it is a potential therapeutic target against flavivirus infection.