Regulation between AIM2/BLIMP-1 in the activation of dendritic cells during in vitro and in vivo L. infantum infection.

• Grant number: 24/03237-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2024
• End date: December 31, 2024
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Vanessa Carregaro Pereira
• Grantee: Lucas Stevanin Timoteo
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

The complexity of the immune response against Leishmania infantum, protozoa parasites causative of visceral leishmaniasis (VL) in Brazil, is represented by the high diversity of factors involved in the parasite-host relationship, focusing on the immune response. The cellular immune response is involved in the clinical outcome, in which the resistance profile is associated to the Th1-lymphocytes profile leading the phagocyte microbicidal mechanisms, while the Th2-pattern and Tregs to susceptibility by triggering the suppressive mechanisms and inactivation of the effector immune response, leading to parasites persistence. In this sense, several innate components present a potential role in directing the cellular immune response, as is the case of cytosolic receptors that form the inflammasome, which often behave in such a way as to activate or regulate pro-inflammatory cytokines (e.g. IL-1²/± and IL-18). AIM2 is one of these cytosolic receptors, working as a dsDNA sensor, very well characterized in infections by bacteria and viruses, but little described in infections by Leishmania spp. parasites. Previous data obtained by our group demonstrate a relationship between AIM2 and the regulatory pathways on inflammation, mainly in the modulation of dendritic cells (DCs) during murine infection. The absence of AIM2 promotes a pronounced Th1-inflammation due to the activation of DCs. However, the DC subtype (plasmacytoid, myeloid, resident or migratory) that is preferentially target by AIM2 remains to be elucidated. As a regulatory mechanism, we propose that AIM2 acts on BLIMP-1, a transcriptional repressor, activating its regulatory functions on DCs and impacting the Th1 inflammatory response in experimental VL, the central objective of the present proposal.