Investigating the impact of inflammasome-induced pyroptosis on visceral leishmaniasis in mice.

The Nlrp3 inflammasome is a protein complex that responds to microbial structures leading to the activation of a protease called caspase-1 that induces a form of cell death termed pyroptosis. This cell death mode facilitates secretion of the pro-inflammatory cytokines IL-1β and IL-18 that contribute to mounting efficient inflammatory responses against infections. Leishmaniasis is a major neglected parasitic disease caused by Leishmania species that can lead to a broad range of clinical manifestations ranging from cutaneous and mucocutaneous inflammation to a lethal visceral leishmaniasis (VL). Mouse model observations demonstrated an involvement of Nlrp3 inflammasome signalling in cutaneous leishmaniasis, and patient observations showed that the inflammasome-generated cytokines IL-1β and IL-18 correlate with VL severity. However, the effect of downstream Nlrp3-induced pyroptosis on the more severe VL disease has not been investigated. Moreover, recent observations showed that the ability of VL parasites display different infection kinetics in different cell types and at different stages of the infection, suggesting that pyroptosis could represent one of the intracellular host defence mechanisms responsible for determining parasite survival and spreading. Therefore, in this project we aim to reveal how Nlrp3-induced pyroptosis affects visceral leishmaniasis in mice. More specifically, we will aim to reveal in which cell types VL parasites induce pyroptosis as well as to reveal the in vivo function of pyroptosis during a model of treatment relapse VL in mice. In addition, we will aim to reveal how pyroptosis correlates with the in vivo infection kinetics of VL parasites during pathogenesis, and how this form of cell death in turn impacts on the parasite. On the long term, this project might facilitate designing better cell type and disease stage specific VL treatments. In addition, mapping the capacities of different myeloid cell types for undergoing pyroptosis during VL will generate general knowledge with implications beyond parasitic infections such as in other types of infections and in inflammatory diseases associated with inflammasome activation.

Keywords:CELL FATE, INFLAMMASOME, INFECTIOUS DISEASES

Disciplines:Innate immunity, Infectious diseases, Parasitology, Cell death