Integration among receptors of innate immunity (TLR/IL-1R/IL-18R/AIM2) in the modulation of the immune response induced during Visceral Leishmaniasis

Abstract

This proposal is a continuation of a research line that we have developed. Recently, we had made progress understanding the role of innate immunity receptors, such TLRs, modulating the immune response during experimental VL. While the signaling pathways mediated by TLR2 and TLR9 appear to promote the development of an effector immune response, which controls parasite replication, the pathway mediated through TLR4 acts to hamp the inflammation, preventing the development of immunopathology. Since different receptors, such as the cytosolic - AIM2 and the membranes- IL-1R and IL-18R, share several intracellular molecules with TLRs, it is necessary to evaluate whether they act in an integrated-manner, promoting or inhibiting the immune response and thus, contributing to the determination of clinical forms of the disease. Another important aspect is the possible participation of IL-1± in the regulation of membrane integrity of the intestinal epithelium, in the prevention of intestinal dysbiosis and consequent interference in the systemic cytokines storm, pathognomonic factors found in patients with severe forms of the disease. In this context, the interchange between these systems may result in synergistic or antagonistic interactions, leading to the enhancement of host defense or the regulation of exacerbated inflammatory responses. Thus, the present project has as central axis to understand the immunological mechanisms that may be involved in the severity of Visceral Leishmaniasis, with emphasis on receptors and innate cytokines and their possible cooperation in the intracellular signaling that manages the adaptive immune response, relating them to development of clinical manifestations of VL patients (AU)