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bioRxiv · 10.1101/2024.10.21.619374

Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of Leishmania donovani

Pradhan, S.·Dhar, D.·Manna, D.·Chakraborty, S.·Bhattacharyya, A.·Chauhan, K.·Mukherjee, R.·Sen, A.·Pandey, K.·Das, S.·Mukherjee, B.
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Abstract

The management of Leishmania donovani (LD), responsible for fatal visceral leishmaniasis (VL), faces increasing challenges due to rising drug-unresponsiveness, leading to increasing treatment failures. While hypolipidemia characterizes VL, LD, a cholesterol auxotroph, relies on host lipid scavenging for its intracellular survival. The aggressive pathology, in terms of increased organ parasite load, observed in hosts infected with antimony-unresponsive-LD (LD-R) as compared to their sensitive counterparts (LD-S), highlights LD-Rs heightened reliance on host lipids. Here we report that LD-R-infection promotes fluid-phase endocytosis in the host, selectively accumulating neutral lipids while excluding oxidized-LDL. LD-R enhances the fusion of endocytosed LDL-vesicles with its phagolysosomal membrane and inhibits cholesterol mobilization from these vesicles by suppressing NPC-1. This provides LD-R amastigotes with excess lipids, supporting their rapid proliferation and membrane synthesis. This excess LDL-influx leads to an eventual accumulation of neutral lipid droplets around LD-R amastigotes, thereby increasing their unresponsiveness towards Amphotericin-B, a second-line amphiphilic antileishmanial. Notably, VL patients showing relapse with Amphotericin-B treatment exhibited significantly lower serum LDL and cholesterol than cured cases. Treatment with Aspirin, a lipid droplet blocker, reduced lipid droplets around LD-R amastigotes, restoring Amphotericin-B responsiveness.

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Pradhan, S., Dhar, D., Manna, D., Chakraborty, S., Bhattacharyya, A., Chauhan, K., Mukherjee, R., Sen, A., Pandey, K., Das, S., Mukherjee, B.. 2024-10-22. Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of Leishmania donovani. https://doi.org/10.1101/2024.10.21.619374

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