Host Cell Lipid Bodies Triggered by Trypanosoma cruzi Infection and Enhanced by the Uptake of Apoptotic Cells Are Associated With Prostaglandin E2 Generation and Increased Parasite Growth

Abstract

Lipid bodies (lipid droplets) are lipid-rich organelles with functions in cell metabolism and signaling. Here, we investigate the mechanisms of Trypanosoma cruzi-induced lipid body formation and their contributions to host-parasite interplay. We demonstrate that T. cruzi-induced lipid body formation in macrophages occurs in a Toll-like receptor 2-dependent mechanism and is potentiated by apoptotic cell uptake. Lipid body biogenesis and prostaglandin E₂ (PGE₂) production triggered by apoptotic cell uptake was largely dependent of α(v)β₃ and transforming growth factor-β signaling. T. cruzi-induced lipid bodies act as sites of increased PGE synthesis. Inhibition of lipid body biogenesis by the fatty acid synthase inhibitor C75 reversed the effects of apoptotic cells on lipid body formation, eicosanoid synthesis, and parasite replication. Our findings indicate that lipid bodies are highly regulated organelles during T. cruzi infection with roles in lipid mediator generation by macrophages and are potentially involved in T. cruzi-triggered escape mechanisms.

TLR6-Driven Lipid Droplets in Mycobacterium leprae-Infected Schwann Cells: Immunoinflammatory Platforms Associated with Bacterial Persistence

“…This suggests a role for newly formed LDs in intracellular M. leprae survival within the nerve. In support of the hypothesis that LDs are involved in M. leprae survival, pathogen-induced host LD formation has been associated with intracellular pathogen survival advantages in hepatitis C virus (51,52), dengue (46), T. cruzi (48), and BCG infections (11,32). The role of LD inhibition in leading to M. leprae's improved killing ability of SCs may occur secondary to the inhibition of PGE 2 production and modulation of the cytokine milieu.…”

“…In different cell systems, LD biogenesis was shown to require new lipid synthesis in a mechanism tightly regulated by FAS (45)(46)(47). Accordingly, the FAS inhibitor C-75 significantly inhibited LD formation induced by BCG, Trypanosoma cruzi, and dengue virus infection (32,46,48). Although not a cyclooxygenase inhibitor, C-75-induced LD inhibition led to inhibition of PGE 2 production.…”

Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

“…Thus, it is possible that treatment with the combinations potentiates autophagy, particularly mitophagy. Finally, several studies have demonstrated the presence of lipid bodies, lipid-rich organelles that function in cell metabolism and signaling (58,59), in parasites treated with sterol biosynthesis inhibitors, and it has been shown in several cases that these alterations sometimes are related with an abnormal accumulation of endogenous intermediates produced by the inhibition of ergosterol biosynthesis (16,17,21). In this work, we found that combination treatments with E5700 and ITZ or POSA caused a significant increase of lipid bodies, similar to the effects of azoles alone at their MICs.…”

Trypanosoma cruziInfection and Host Lipid Metabolism

“…Melo showed that, during acute T. cruzi infection, there is a prominent increase in the number of lipid bodies in macrophages [26]. This increase in lipid body formation correlated with increased parasite load in vivo [27]. It was further demonstrated that the induction of lipid body formation during T. cruzi infection was Toll-like receptor (TLR-2) dependent and was enhanced by the uptake of apoptotic cells, which causes macrophage to interact with α v β 3 integrin and activates TGF- β -dependent lipid body formation [27, 28].…”