Unveiling Lipid Signaling in Leishmania: Mechanisms and Implications for Therapeutics

Abstract: Lipid signaling plays a crucial role in the cellular survival, virulence, pathogenicity, and progression of leishmaniasis, which is a significant public health concern. The lack of effective therapeutics and high toxicity, and drug resistance of existing chemotherapy have delayed therapy progression and have proven to be overall insufficient for controlling disease load worldwide. This review explores the intricate mechanisms by which lipid signaling contributes to Leishmania biology and highlights its potential as a therapeutic target. A range of cellular processes in the Leishmania parasite, including membrane dynamics, energy metabolism, and immune evasion, depends on lipid signaling. Key components of the lipid signaling pathway, such as eicosanoids, sphingolipids & glycosyl-phosphoinositides, have been studied to make significant contributions in this area. Sphingolipids are implicated in the stress response and programmed cell death, whereas phosphoinositide signaling serves by acting as the anchor for the parasite to enter and survive within host macrophages. Eicosanoids, on the other hand, are a particularly intriguing target for therapeutic intervention due to their dual role in regulating both host immune responses and parasite survival. Since eukaryotic protein kinases control every critical process necessary for Leishmania viability and the completion of the parasitic life cycle, including cell-cycle progression, differentiation, and virulence, their inhibition is predicted to modify the disease. This review provides a thorough overview of lipid signaling molecules and their roles in Leishmania by delving into the recent developments in the field. It also explores the therapeutic possibilities of focusing on the eukaryotic protein kinases, emphasizing current therapies and repurposing of existing drugs. A better understanding of these pathways and strategies can potentially lead to improved patient outcomes and treatment in leishmaniasis.