Long-term hematopoietic stem cells as a parasite niche during treatment failure in visceral leishmaniasis

Area of Science:

• Parasitology
• Immunology
• Stem Cell Biology

Background:

• Visceral leishmaniasis (VL) treatment faces challenges due to drug resistance and relapses.
• Identifying persistent parasite reservoirs is crucial for understanding therapeutic failure.

Purpose of the Study:

• To investigate the cellular niche and molecular mechanisms underlying persistent Leishmania infections and treatment failure.
• To explore potential therapeutic targets for overcoming drug resistance in VL.

Main Methods:

• Established a rodent model with bioluminescent/fluorescent Leishmania reporter lines.
• Conducted in vivo drug screening, immunophenotyping, and transcriptomics.
• Analyzed hematopoietic stem cells (HSCs) for parasite burden and transcriptional profiles.

Main Results:

• Identified long-term hematopoietic stem cells (LT-HSCs) as a niche with high parasite loads in bone marrow.
• LT-HSCs exhibit increased tolerance to antileishmanial drugs and are a source of relapse.
• Defined a 'StemLeish' transcriptional signature in LT-HSCs, involving TNF/NF-κB and TGF-β signaling pathways, with reduced oxidative burst.
• Observed overlap between cross-species transcriptomes and human VL/HIV co-infection data.

Conclusions:

• LT-HSCs serve as a drug- and oxidative stress-resistant niche for Leishmania persistence.
• Conserved transcriptional reprogramming in LT-HSCs contributes to treatment failure in VL.
• Targeting the LT-HSC niche presents a potential therapeutic strategy for leishmaniasis.