Immunomodulatory Effect of 7-oxo-DHEA on Mycobacterium tuberculosis-Specific Responses in the context of HIV Coinfection.

MARIA BELEN VECCHIONE; CLAUDIA DEL CARMEN MELUCCI GANZARAIN; GUADALUPE VERONICA SUAREZ; OMAR SUED; NATALIA LAUFER; JORGE BARRIOS PAYÁN; DULCE MATA ESPINOSA; BRENDA MARQUINA; ANDREA CLAUDIA BRUTTOMESSO; ROGELIO HERNANDEZ PANDO; MARIA FLORENCIA QUIROGA

Simposio; Tuberculosis: Translating Scientific Findings for Clinical and Public Health Impact (X7); 2018

Keystone Symposia

Tuberculosis treatment in HIV+ people is tough due to the failure of host defense mechanisms. Thus, new therapeutic ideas are needed. Knowing the immunostimulant activity of dehydroepiandrosterone (DHEA), we studied its derivative 7-oxo-DHEA as a modulator of Mycobacterium tuberculosis (Mtb)-specific responses in HIV-TB coinfection. Methods: Healthy donors (HD) and HIV-TB people were recruited. We measured plasma hormone concentrations by HPLC-MS/MS and studied the effect of 7-oxo-DHEA on isolated PBMCs, by thymidine incorporation and ELISA. Afterward, we infected THP-1 human macrophages with Mtb H37Rv in presence of 7-oxo-DHEA and evaluated phagocytosis and colony forming units (CFU). Finally, Mtb-infected mice were treated with 7-oxo-DHEA by subcutaneous and intratracheal administration from 60 to 90 days post-infection. Lungs and spleen were used for CFU counting. Results: We found statistically higher plasma levels of DHEA and 7-oxo-DHEA in HIV-TB persons. Plasmatic 7-oxo-DHEA positively correlated with absolute and nadir CD4+ T cell counts and with TB restricted to the lungs. Also, 7-oxo-DHEA increased cell proliferation and stimulated a Th1-like cytokine profile, increasing IFN-γ and TNF- levels, without suppressing IL-10 and reducing IL-17A. Infected macrophages exposed to 7-oxo-DHEA showed higher phagocytic capacity and improved control of bacterial growth. Tuberculous mice treated with 7-oxo-DHEA presented reduced bacterial load in lung and spleen and an augmented survival. Conclusions: Due to its immunoadjuvant activity, we proposed that 7-oxo-DHEA could be used to enhance TB treatment, improving the quality of life of patients.