Evaluation of the role of Ninj1 in the modulation of cell death in Leishmania-infected macrophages and its participation in inducing the immune response in vivo

Abstract

Leishmaniasis is caused by the obligate intracellular protozoan of the genus Leishmania, a disease that affects more than one million people and causes 70,000 deaths per year. The parasites replicate within macrophages and negatively modulate several signaling pathways and cell death in these cells, as an important evasion mechanism. Members of the NOD family of receptors, including NLRP3, have emerged as important sensors for microbes and cell damage. Previous studies have demonstrated that NLRP3/AIM2/NLRP1 receptors and IL-1² secretion contribute to the protective and pathological results in Leishmaniasis, suggesting these pathways as a future target in the development of therapeutic and prophylactic tools. In addition, the activation of the inflammasome also promotes a potent inflammatory mode of lytic cell death called pyroptosis. There are two sequential steps for pyroptosis: the initial formation of a small pore of the plasma membrane that requires the participation of GSDMD and causes the release of IL-1² and non-selective ion flows, and the subsequent plasma membrane rupture. Recently, it was demonstrated that for membrane rupture is necessary the participation of a protein called Ninj1 that promotes the cell collapse, releasing lactate dehydrogenase and DAMPs. Ninj1 is an evolutionarily conserved and broadly expressed protein that functions as an adhesion molecule associated with inflammation, tumor suppression and essential in lytic cell death, so it can play an important role during pathophysiological processes. It is important to highlight that despite of inflammasome to be activated, Leishmania parasites inhibit quite effectively the cell death process. Therefore, we will work with the hypothesis that Leishmania modulates the normal biology of Ninj1 to keep the viability of the cells that support parasitic replication, and that this protein plays an important role in the host-pathogen interaction. Thus, the present project aims to investigate and understand the role of Ninj1 in Leishmania infection assessing the expression and behavior of this molecule, additionally evaluating its importance in resistance and pathology by this protozoan. (AU)