The role of gasdermin-D in the activation of inflammasome in response to Leishmania (L.) amazonensis infection

Abstract

Leishmaniasis is a neglected tropical disease caused by intracellular protozoa of the genus Leishmania spp. The parasite primarily infects macrophages, which are phagocytic cells of the innate immune system, and play an important role in the elimination of intracellular pathogens. Leishmania amazonensis is related to the development of cutaneous manifestations that can be divided into cutaneous and mucocutaneous. Papers published by our research group, suggest a significant involvement of NLRP3/ASC inflammasome in the control of Leishmania infection in mice (Lima-Junior et al., 2013, 2017 and Zamboni & Lima-Junior, 2015). After the activation of this inflammasome, cleavage of gasdermin-D (GSDMD) and its association in the cell's cytoplasmic membrane occurs, in a process called pyroptosis. This programmed cell death has already been described as being important for the elimination of intracellular bacteria. Due to the importance of the recognition of this parasite by the innate receptors of the immune system, for control of Leishmania replication, the objective of this project is to investigate the role of GSDMD during the activation of the different inflammasomes in response to Leishmania amazonensis infection. The specific objectives are: (i) to evaluate the activation of GSDMD in response to Leishmania infection; (ii) to evaluate the importance of different inflammasomes in the activation of GSDMD; (iii) to evaluate the participation of Naip1, Naip2 and Naip5 in the activation of the inflammasome of NLRC4 and GSDMD; (iv) to evaluate the participation of human Naip (hNAIP) in the activation of the inflammasome of NLRC4 and activation of GSDMD; (v) evaluate the intracellular location of GSDMD in response to L. amazonensis infection; and (vi) analyze the importance of GSDMD in controlling replication in macrophages in vitro and in vivo. This work has great scientific relevance because the understanding of the role of GSDMD during infection by Leishmania spp. will allow the understanding of important aspects related to the pathogenesis of the disease and host responses, besides opening promising prospects for the identification of targets for drugs more efficient in the treatment of Leishmaniasis. (AU)