Long-term hematopoietic stem cells as a parasite niche during treatment failure in visceral leishmaniasis
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
Communications biology - 5(2022), 1 vom: 25. Juni, Seite 626 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dirkx, Laura [VerfasserIn] |
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| Links: |
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| Themen: |
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| Anmerkungen: |
Date Completed 28.06.2022 Date Revised 17.08.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s42003-022-03591-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM342736558 |
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| 245 | 1 | 0 | |a Long-term hematopoietic stem cells as a parasite niche during treatment failure in visceral leishmaniasis |
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| 500 | |a Date Revised 17.08.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 700 | 1 | |a Hendrickx, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Merlot, Margot |e verfasserin |4 aut | |
| 700 | 1 | |a Bulté, Dimitri |e verfasserin |4 aut | |
| 700 | 1 | |a Starick, Marick |e verfasserin |4 aut | |
| 700 | 1 | |a Elst, Jessy |e verfasserin |4 aut | |
| 700 | 1 | |a Bafica, André |e verfasserin |4 aut | |
| 700 | 1 | |a Ebo, Didier G |e verfasserin |4 aut | |
| 700 | 1 | |a Maes, Louis |e verfasserin |4 aut | |
| 700 | 1 | |a Van Weyenbergh, Johan |e verfasserin |4 aut | |
| 700 | 1 | |a Caljon, Guy |e verfasserin |4 aut | |
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