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

Dirkx, Laura; Hendrickx, Sarah; Merlot, Margot; Bulté, Dimitri; Starick, Márick R; Elst, Jessy; Báfica, André; Ebo, Didier G.; Maes, Louis; Weyenbergh, Johan Van; Caljon, Guy

doi:10.1038/s42003-022-03591-7

Cited by 22 publications

(35 citation statements)

References 91 publications

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“…Blocking studies in future will reveal the mechanism of entry of L. donovani parasites into HSCs. 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: 86%

“…Many public resources, such as ImmGen and the Human Cell Atlas, provide the required data for the desired cell populations, yet there is no information available for parasitized cell types, which would be required to deconvolve infected from uninfected cells. Logically, past attempts of deconvolution have compared results between infected and uninfected tissue (Dirkx et al, 2022). However, deconvolution of cell populations derived an infected host using prior knowledge of cell types from uninfected host remains a challenge of this approach.…”

Section: Discussionmentioning

confidence: 99%

“…Dual RNA-Seq analysis that targeted both host and parasite transcriptomes by bulk RNA-seq in liver and spleen of L. donovani and L. infantum infected mouse models showed potential differences in the pathophysiology in the two infections (Forrester et al, 2022). Transcriptional analysis using in silico cell type deconvolution identified a gene expression signature that was conserved in VL cohorts in India, Ethiopia and Brazil (Dirkx et al, 2022). scRNA-Seq of the cells isolated from L. major infected mice identified recruited and skin resident heterogenous populations (Venugopal et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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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: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…There is also evidence of persister forms in leishmaniasis. PKDL is an example of relapse occurring after treatment and apparent cure of VL with antimonials in India [ 122 , 123 ].…”

Section: Current Treatments Against Trypanosomatidsmentioning

confidence: 99%

Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates

et al. 2023

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Due to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases.

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“…Mef2c has been demonstrated to be associated with enrichment of classical activated macrophages that is M1 and promotes pro-inflammatory cytokine production in leishmaniasis (Dirkx et al, 2022), it was observed from patient samples that synthesis of Mef2c is associated with NFAT5 canonical pathway which also in turn regulates NFAT5 mediated immune response, TNFα is the upstream regulator of MEF2C (Salih et al, 2017). Another transcription factor which was enriched through TFTG network was Isl1, although much is not known about the role of this gene in leishmaniasis nonetheless, it consists of LIM domain is essential for regenerating T cell in spleen in leishmaniasis (Golub et al, 2018).…”

Section: Nfat5 Controls Cellular Signaling and Epigenetically Regulat...mentioning

confidence: 99%

Single cell ATAC sequencing identifies sleepy macrophages during reciprocity of cytokines inL.majorinfection

Khandibharad¹,

Kharat²,

Singh³

2023

Preprint

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Hallmark for macrophages is their ability to possess plasticity which enables them to respond to changing microenvironment. Leishmania takes use of the phenotypic plasticity of macrophages to create favorable position for intracellular survival and persistent infection through regulatory cytokine like IL10. However, these effector cells can eliminate infection through modulation of critical cytokines such as IL12 and key players involved in its production. Using sophisticated tool of single cell ATAC sequencing we analyzed the regulatory axis of IL10 and IL12 in time dependent manner for L.major infection in macrophages. We recognized the cellular heterogeneity post infection with the regulators of IL10 and IL12 and observed a reciprocal relationship between them. Our prominent findings also exposed sleepy macrophages and its role in IL10 and IL12 reciprocity. To summarize, role of NFAT5 was vital in identification of sleepy macrophages which is a transient state where transcription factors controlled the epigenetic remodeling and expression of genes involved in pro-inflammatory cytokine production and recruitment of immune cells.

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

Cited by 22 publications

References 91 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

Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates

Single cell ATAC sequencing identifies sleepy macrophages during reciprocity of cytokines inL.majorinfection

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