Evaluation of the role of inflammasomas and their signaling pathways in murine experimental infection by Leishmania infantum

Abstract

The protozoan parasite of the genus Leishmania is the causative agent of leishmaniasis, which comprises a series of clinical manifestations. Visceral Leishmaniasis (VL) is the most serious form of the disease, estimated to cause 500,000 new cases and 60,000 deaths per year. It is also reported that 90% of cases occur in India, Bangladesh, Nepal, Sudan and Brazil. Leismania infantum is responsible for causing disease in the Mediterranean and South and Central America. In Brazil, VL is considered zoonotic, since the transmission of the disease is supported by mammalian reservoirs such as domestic dogs. It is also noted that in most human VL it occurs in immunocompromised children or adults. In response to microbial molecules from intracellular pathogens such as Leishmania, protein complexes called inflamosomes are assembled in the cytoplasm of innate immune systems. Once assembled, the inflammasomes induce the secretion of inflammatory cytokines. This process occurs concurrently with the induction of a specific and programmed form of inflammatory cell death. Therefore, this process favors the initiation of inflammatory processes in infected or damaged tissues, contributing to the elimination of the pathogen. In this sense, the development of the present research proposal may generate knowledge about the role of inflammasomes in visceral disease caused by L. infantum.In this project we intend to evaluate the participation of different inflammasomes in the control of L. infantum replication in vivo. For this purpose, it is firstly intended to compare the infection rate of different clinical isolates of L. infantum (eg HU-USF 8, HU-USF 14 and NCL). After identifying the clinical isolate that causes the best infection rate, reporter genes such as GFP, RFP or luciferase will be expressed in this parasite. Thus, it will be possible to evaluate and compare L. infantum reporter infection in knockout mice: Aim2-/-, Nlrp3-/-, Asc-/- and Casp1-/- and consequently evaluate the importance of inflammasome in infection. and the response against these parasites. Comparisons with Leishmania amazonensis infection, which is a very well established Leishmania species for mouse infections. (AU)