Long-term hematopoietic stem cells as a parasite niche during treatment failure in visceral leishmaniasis
Laura Dirkx, Sarah Hendrickx, Margot Merlot, Dimitri Bulté, Márick Rodrigues Starick, Jessy Elst, André Báfica, Didier G. Ebo, Louis Maes, Johan Van Weyenbergh, Guy Caljon
Abstract
Given the discontinuation of various first-line drugs for visceral leishmaniasis (VL), large-scale in vivo drug screening, establishment of a relapse model in rodents, immunophenotyping, and transcriptomics were combined to study persistent infections and therapeutic failure. Double bioluminescent/fluorescent Leishmania infantum and L. donovani reporter lines enabled the identification of long-term hematopoietic stem cells (LT-HSC) as a niche in the bone marrow with remarkably high parasite burdens, a feature confirmed for human hematopoietic stem cells (hHSPC). LT-HSC are more tolerant to antileishmanial drug action and serve as source of relapse. A unique transcriptional 'StemLeish' signature in these cells was defined by upregulated TNF/NF-κB and RGS1/TGF-β/SMAD/SKIL signaling, and a downregulated oxidative burst. Cross-species analyses demonstrated significant overlap with human VL and HIV co-infected blood transcriptomes. In summary, the identification of LT-HSC as a drug- and oxidative stress-resistant niche, undergoing a conserved transcriptional reprogramming underlying Leishmania persistence and treatment failure, may open therapeutic avenues for leishmaniasis.