Infection of hematopoietic stem cells by Leishmania infantum increases erythropoiesis and alters the phenotypic and functional profiles of progeny

Carvalho-Gontijo, Raquel; Moreira, Diana; Resende, Mariana; Costa-Silva, Matheus Fernandes; Peruhype-Magalhães, Vanessa; Ribeiro, Cláudia Maria Franco; Ribeiro, Daniel Dias; Silvestre, Ricardo; Cordeiro-da-Silva, Anabela; Martins‐Filho, Olindo Assis; Teixeira-Carvalho, Andréa

doi:10.1016/j.cellimm.2017.10.016

Cited by 12 publications

(8 citation statements)

References 31 publications

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“…Recent studies showing the uptake of L. donovani/L. infantum parasites in human (Carvalho-Gontijo et al, 2018) and murine HSCs (Dirkx et al, 2022) further validates our results obtained by dual scRNA-Seq analysis. Our in vivo studies from Balb/C mice that has been infected with L. donovani DsRed parasites for 9 months showed that Ter-119-CD11b-CD45R-CD5-CD3-Gr1-Sca-1+c-Kit+ HSCs remain infected with the parasites strengthens the hypothesis that HSCs maybe a source of persistent infection due to their longevity.…”

Section: Discussionsupporting

confidence: 88%

Dual scRNA-Seq analysis reveals rare and uncommon parasitized cell populations in chronic L. donovani infection

Karagiannis¹,

Gannavaram²,

Verma

et al. 2022

Preprint

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Although phagocytic cells are documented targets of Leishmania parasites, it is unclear whether these parasites can infect other cell types. In this study, we describe a computational approach that exploits scRNA-seq to simultaneously analyze the transcriptomic signatures of the host cell and to identify rare and uncommon cells that harbor Leishmania donovani in the spleen and bone marrow. Individual cells were annotated as parasitized based on the presence of L. donovani transcripts that were detected with high accuracy. This unbiased approach allowed identification of heterogenous parasitized cell populations that cannot be detected by conventional methods. Consistent with previous studies, analysis of spleen cells isolated from L. donovani infected mice revealed inflammatory monocytes as the dominant parasitized cells. In addition, megakaryocytes, basophils , and NK cells were found to be the rare cells infected in the spleen. Unexpectedly, hematopoietic stem cells (HSCs), not known to be phagocytic, were the dominant cells parasitized cell in the bone marrow. In addition, eosinophils, megakaryocytes, and basal cells were the rare bone marrow cells found to be infected. scRNA-seq analysis revealed known phagocytic receptors FcγR and CD93 are expressed on HSCs . In vitro studies using purified HSCs showed that these cells can phagocytize L. donovani. Parasitized HSCs were also detectable in the bone marrow of mouse infected with L donovani. . This unbiased dual scRNA-seq approach enables identification of rare and uncommon parasitized cells that could be involved in pathogenesis, persistence, and protective immunity. Further, such approach could be used to study pathogenesis of other infectious agents.

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Section: Discussionsupporting

confidence: 88%

Dual scRNA-Seq analysis reveals rare and uncommon parasitized cell populations in chronic L. donovani infection

Karagiannis¹,

Gannavaram²,

Verma

et al. 2022

Preprint

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“…In a study by Pinto et al that did not include a progenitor enrichment 19 , no infected LT-HSC were detected after 28 days of infection with Td-Tomato transgenic L. donovani . In contrast, an in vitro study by Carvalho-Gontijo et al 68 documented the presence of L. infantum in human CD34 + stem cells. According to Cotterell et al 69 , CD34 + progenitor cells do not appear to be targets for Leishmania infection.…”

Section: Discussionmentioning

confidence: 90%

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

et al. 2022

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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.

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“…The authors further con rmed the parasite's viability highlighting the importance of the BM stroma during VL infection. A study by Carvalho-Gontijo et al [43] also documented the presence of L. infantum in human CD34+ stem cells. Our study further pinpointed the exact cellular tropism in the various stem cell and progenitor subsets.…”

Section: Discussionmentioning

confidence: 89%

Long-term Hematopoietic Stem Cells as Sanctuary Niche during Treatment Failure in Visceral Leishmaniasis

Dirkx¹,

Hendrickx²,

Maes³

et al. 2021

Preprint

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The increasing frequency of treatment failure in visceral leishmaniasis (VL) has already resulted in discontinuation of various first-line drugs. Although most studies focus on associations with parasitic drug resistance, a knowledge gap remains about other factors determining cure versus relapse. The present study used double bioluminescent/fluorescent Leishmania infantum and L. donovani reporter lines to study relapse at the tissue and cellular level. In combination with 123 different treatments in golden Syrian hamsters, the observations provide evidence of parasites surviving in the bone marrow (BM), identifying this tissue as a sanctuary site from where the host can be recolonized. Long-term hematopoietic stem cells (LT-HSC; Lin- Sca1 + cKit + CD48- CD150+) were found to become readily infected through invasion rather than phagocytosis. Compared to other BM cells and macrophages, LT-HSCs constitute a hospitable cellular niche with low nitric oxide and reactive oxygen species levels and harbouring enormous parasite burdens. Moreover, we found that infected LT-HSCs are less sensitive to antileishmanial reference drugs in comparison to macrophages. Given the important clinical implications for the current field situation of increasing post-treatment relapse rates, this study represents an essential step by identifying the BM cellular niches responsible for Leishmania persistence and treatment failure.

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Infection of hematopoietic stem cells by Leishmania infantum increases erythropoiesis and alters the phenotypic and functional profiles of progeny

Cited by 12 publications

References 31 publications

Dual scRNA-Seq analysis reveals rare and uncommon parasitized cell populations in chronic L. donovani infection

Dual scRNA-Seq analysis reveals rare and uncommon parasitized cell populations in chronic L. donovani infection

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

Long-term Hematopoietic Stem Cells as Sanctuary Niche during Treatment Failure in Visceral Leishmaniasis

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