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

Karagiannis, Konstantinos; Gannavaram, Sreenivas; Verma, Chaitenya; Pacheco-Fernandez, Thalia; Bhattacharya, Parna; Nakhasi, Hira L.; Satoskar, Abhay R.

doi:10.1016/j.celrep.2023.113097

Cited by 12 publications

(3 citation statements)

References 56 publications

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“…LT-HSC become readily infected with extreme parasite burdens accompanied with low reactive oxygen species (ROS) and nitric oxide (NO) levels and a specific Stemleish transcriptional profile [ 16 ]. A recent dual-scRNA-seq analysis in a chronic L. donovani infection model corroborated the proportional importance of HSC, identifying them as the main parasitized cell type in the bone marrow [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites

Dirkx,

Van Acker,

Nicolaes

et al. 2024

PLoS Pathog

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Addressing the challenges of quiescence and post-treatment relapse is of utmost importance in the microbiology field. This study shows that Leishmania infantum and L. donovani parasites rapidly enter into quiescence after an estimated 2–3 divisions in both human and mouse bone marrow stem cells. Interestingly, this behavior is not observed in macrophages, which are the primary host cells of the Leishmania parasite. Transcriptional comparison of the quiescent and non-quiescent metabolic states confirmed the overall decrease of gene expression as a hallmark of quiescence. Quiescent amastigotes display a reduced size and signs of a rapid evolutionary adaptation response with genetic alterations. Our study provides further evidence that this quiescent state significantly enhances resistance to treatment. Moreover, transitioning through quiescence is highly compatible with sand fly transmission and increases the potential of parasites to infect cells. Collectively, this work identified stem cells in the bone marrow as a niche where Leishmania quiescence occurs, with important implications for antiparasitic treatment and acquisition of virulence traits.

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Section: Introductionmentioning

confidence: 99%

Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites

Dirkx,

Van Acker,

Nicolaes

et al. 2024

PLoS Pathog

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“…Recent advancements in single-cell RNA sequencing (scRNA-seq) have been instrumental in revealing diverse gene expression patterns across different cell types. , A key goal in analyzing scRNA-seq data is the identification of rare cells, a task that is both crucial and challenging. − Detecting rare cells such as endothelial progenitor cells, tumor stem cells, and invariant natural killer T cells is vital for understanding the immune response in diseases, especially cancer, and for studying cancer’s development. , Endothelial progenitor cells, for example, are important markers for tumor blood vessel growth. Tumor stem cells are central to the formation and spread of cancer, and invariant natural killer T cells provide critical defense against pathogens such as Mycobacterium tuberculosis . − These insights are essential for a deeper understanding of tissue biology in health and disease …”

Section: Introductionmentioning

confidence: 99%

Connectivity Network Feature Sharing in Single-Cell RNA Sequencing Data Identifies Rare Cells

Wang,

Li,

Liu

et al. 2024

J. Chem. Inf. Model.

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Single-cell RNA sequencing is a valuable technique for identifying diverse cell subtypes. A key challenge in this process is that the detection of rare cells is often missed by conventional methods due to low abundance and subtle features of these cells. To overcome this, we developed SCLCNF (Local Connectivity Network Feature Sharing in Single-Cell RNA sequencing), a novel approach that identifies rare cells by analyzing features uniquely expressed in these cells. SCLCNF creates a cellular connectivity network, considering how each cell relates to its neighbors. This network helps to pinpoint coexpression patterns unique to rare cells, utilizing a rarity score to confirm their presence. Our method performs better in detecting rare cells than existing techniques, offering enhanced robustness. It has proven to be effective in human gastrula data sets for accurately pinpointing rare cells, and in sepsis data sets where it uncovers previously unidentified rare cell populations.

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“…Visceral leishmaniasis presents as irregular bouts of fever, weight loss, enlargement of the spleen and liver, and anemia [1]. In addition to infection of monocytes and macrophages, L. donovani infect hematopoietic stem cells, megakaryocytes and other cell lineages that are not known to be phagocytic [2]. Once inside mammalian cells, Leishmania spp.…”

Section: Introductionmentioning

confidence: 99%

Non canonical activation of the ESCRT machinery is required for division ofLeishmania donovaniparasitophorous vacuoles and parasite persistence

Rosero,

Kima

2024

Preprint

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In the mammalian host,L. donovaniare intracellular pathogens that reside in vacuolar compartments (often calledLeishmaniaparasitophorous vacuoles (LdLPVs)). LdLPVs harbor individual parasites that enigmatically divide upon replication of the parasite. In this study, we evaluated the role of the ESCRT machinery in the division of LdLPVs and parasite persistence in infected cells. We found that the ESCRT I member, TSG101 and the ESCRT III members, CHMP2B and CHMP4B are recruited to LdLPVs. In addition, Vps4a, an accessory molecule required for recycling of ESCRT III molecules is also recruited to LdLPVs. Interestingly, infection of cells expressing a dominant negative version of Vps4a that prevents the recycling of ESCRT III revealed that most LdLPVs recruit ESCRT components constitutively. Based on that finding, we proposed that the recruitment of ESCRT molecules to LdLPVs is enabled by the display of the phosphoinositide, PI(3,4)P2 on LdLPVs. To assess the functional importance of recruiting ESCRT molecules to LdLPVs, we monitoredL. donovaniinfections in cells in which ALIX or TSG101 were knocked down. ALIX knock down resulted in LdLPVs that were distended and harbored 4 or more parasites, which is significantly different from LdLPVs in ‘wild type’ macrophages that harbor at most, 2 parasites. Moreover, reduced levels of ALIX resulted in a significant reduction in parasite numbers. These findings revealed the critical role for activation of the ALIX-ESCRTIII axis inL. donovanipathogenesis. This is the first demonstration that the ESCRT machinery plays a role in the division of pseudo-organelles that harbor an intracellular pathogen.SignificanceThe endosomal sorting complex required for transport (ESCRT) machinery plays critical mechanistic roles in physiological processes including cell division (cytokinesis). It can be hijacked to promote the spread and persistence of infectious agents including in the budding of viruses and nutrient acquisition by intracellular pathogens. In this study, we uncover a new role for the ESCRT machinery in the infection of macrophages byLeishmania donovani(Ld). Within infected cells, each Ld parasite resides in aLeishmaniaparasitophorous vacuole (LPV) that enigmatically divides to accommodate daughter parasites. We show that a non-canonical activation of the ESCRT machinery is required for division of LPVs and for parasite persistence. Future studies on the mechanisms for selective activation of the ESCRT machinery would reveal targets for the control of this deadly pathogen.

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

Cited by 12 publications

References 56 publications

Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites

Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites

Connectivity Network Feature Sharing in Single-Cell RNA Sequencing Data Identifies Rare Cells

Non canonical activation of the ESCRT machinery is required for division ofLeishmania donovaniparasitophorous vacuoles and parasite persistence

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