Action of Liver-X Receptor (LXR) agonists on the depletion of myeloid-derived suppressor cells (MDSCs) in the liver of mice infected with the fungus Paracoccidioides brasiliensis.

• Grant number: 22/10707-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2022
• End date: August 31, 2023
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Flávio Vieira Loures
• Grantee: Bianca Vieira dos Santos
• Host Institution: Instituto de Ciência e Tecnologia (ICT). Universidade Federal de São Paulo (UNIFESP). Campus São José dos Campos. São José dos Campos , SP, Brazil
• Associated research grant: 18/14762-3 - Immunosuppression in paracoccidioidomycosis: the regulatory role of myeloid-derived suppressor cells (MDSCs) on host immunity, tissue pathology and genetic adaptation of fungal cells, AP.JP2

Abstract

In paracoccidioidomycosis, the most prevailing systemic mycosis in Latin America, previous studies revealed that the host's immunity is strongly dictated by a diversity of suppressing mechanisms mediated by plasmocytoid dendritic cells, by the 2,3 indoleamine dioxygenase enzyme (IDO1) and regulatory T cells. The activity of IDO1 was demonstrated when orchestrating local and systemic immunosuppressant effects through the recruitment and activation of myeloid derived suppressor cells (MDSCs), cells that regulate immune responses and tissue repair in healthy individuals and expand quickly during a pathological infection. Previous studies demonstrate that the activation of Liver-X receptors (LXR) in vivo, with the utilization of agonists in experimental cancer and tuberculosis models, resulted in an improvement in the immune response of both pathologies. The activity of the MDSCs and their depletion has been target of investigation by our group in PCM murine. It is what took us to proposing this study that seeks to investigate the activity of the agonists to the LXR, GW3965 (GW) and T09013 (T0), about the MDSCs in C57BL/6 mice after two and eight weeks of infection with the fungus Paracoccidiodies brasiliensis. Preliminary data revealed that in lungs (the main infectious focus in PCM), the treatment with GW and T0 was not able to deplete the MDSCs. However, in the liver of these animals, an increase of inflammatory cytokines related to vector lymphocytes has occurred, what may indicate a local effect of these drugs in the MDSCs present in this organ. Thus, the evaluation of the MDSCs present in the liver of infected animals and treated with the aforementioned agonists, may reveal an immunomodulatory action orchestrated by the MDSCs onto other immune system cells in this organ, quite affected by the PCM.