Elevated ergosterol protects Leishmania parasites against antimony-generated stress

Area of Science:

• Parasitology
• Molecular Biology
• Biochemistry

Background:

• Lipids play crucial roles in parasite survival, including signaling, membrane structure, and energy. The impact of drug-induced stress on parasite lipid metabolism and survival is not fully understood.
• Leishmania donovani causes kala-azar, a severe disease, and resistance to drugs like potassium antimony tartrate (PAT) is a growing concern.

Purpose of the Study:

• To investigate the functional roles of lipid changes in Leishmania donovani survival under antileishmanial drug stress.
• To elucidate the relationship between very long-chain fatty acids (VLCFAs), ergosterol, reactive oxygen species (ROS), and parasite susceptibility to potassium antimony tartrate (PAT).

Main Methods:

• Leishmania donovani parasites were treated with potassium antimony tartrate (PAT).
• Gas chromatography-mass spectrometry (GC-MS) was used to analyze lipid profiles.
• Inhibitors of VLCFA biosynthesis, ergosterol biosynthesis, and antioxidants were employed.
• Genetically modified parasites with altered ergosterol levels were used.
• Cell viability assays were performed.

Main Results:

• PAT treatment led to a significant increase in VLCFAs preceding an ergosterol surge in Leishmania parasites.
• Inhibition of ergosterol biosynthesis or VLCFAs reduced parasite viability.
• PAT-induced VLCFA increase correlated with a rise in ROS; ROS inhibition prevented ergosterol accumulation.
• Parasites with low ergosterol levels were more susceptible to PAT, while ergosterol supplementation increased viability.

Conclusions:

• Parasite susceptibility to antimony treatment is determined by cellular ergosterol levels.
• Ergosterol levels are regulated by oxidative stress, which is generated by VLCFAs during antimony treatment.
• Targeting VLCFA or ROS pathways could be a strategy to overcome drug resistance in Leishmania donovani infections.