A spatiotemporally resolved single-cell atlas of the Plasmodium liver stage

Afriat, Amichay; Zuzarte‐Luís, Vanessa; Halpern, Keren Bahar; Buchauer, Lisa; Marques, Sofia; Chora, Ângelo Ferreira; Lahree, Aparajita; Amit, Ido; Mota, Maria M.; Itzkovitz, Shalev

doi:10.1038/s41586-022-05406-5

Cited by 33 publications

(36 citation statements)

References 41 publications

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“…Although both infected and uninfected cells were treated identically in our expression dataset, the use flow sorted hepatoma cells, could create artefactual patterns. Recently a single cell RNA-seq study was published 55 . Although a comprehensive comparison of the mouse and human transcriptomes is outside the scope of this study, the patterns in our cell culture dual RNAseq dataset are supported by single RNA-seq data from mouse liver infected with P. berghei .…”

Section: Discussionmentioning

confidence: 99%

Plasmodium exoerythrocytic parasites redirect trafficking of human proteins to the parasitophorous vacuole

Calla

Mittal

LaMonte

et al. 2022

Preprint

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Changes in host cell morphology and transcription after apicomplexan parasite infection have long been noted, but there have been few studies of the functional consequences of host cell remodeling. Here we show, using time-dependent immunofluorescence microscopy of multiple human cell lines (HFF, HepG2, HC-04, Huh7.5.1 and primary human hepatocytes), infected with multiple Plasmodium species (Plasmodium berghei, P. falciparum and P. vivax (hypnozoites and schizonts)), and antibodies to multiple human proteins (HsNR4A3, HsMUC13, HsGOLGA8A, HsCGA, HsBiP, HsCXCL2), that human protein trafficking is extensively modified in Plasmodium infected cells. Using conventional as well as ultrastructure expansion immunofluorescence microscopy we show that newly-synthesized human proteins are trafficked to the parasitophorous vacuole instead of the infected-cell plasma membrane, nucleus or extracellular space. Universal redirection of human signaling proteins cells the parasitophorous vacuole may provide a mechanistic explanation for how apicomplexan parasites can block host cells response to infection.

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Section: Discussionmentioning

confidence: 99%

Plasmodium exoerythrocytic parasites redirect trafficking of human proteins to the parasitophorous vacuole

Calla

Mittal

LaMonte

et al. 2022

Preprint

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“…7). However, in analyzing smFISH images, the existence of this population was verified as early as 24 hpi 21 . This provided the motivation to use biolord-classify to classify abortive cells within the scRNA-seq data at earlier time points, or in other words, identify the cells that would have progressed to become identifiably abortive at 36 hpi.…”

Section: Biolord Exposes the Transient Trajectory Towards Distinct In...mentioning

confidence: 98%

“…The spatio-temporal single-cell atlas for Plasmodium infection presented above 21 provides an example of such a setting. In their analysis, Afriat et al 21 identified a subpopulation of cells that shows a pattern of vacuole breakdown, termed `abortive hepatocytes`. In the scRNA-seq data, this population was identified only at the latest time point (36 hpi) (Fig.…”

Section: Biolord Exposes the Transient Trajectory Towards Distinct In...mentioning

confidence: 99%

“…This provided the motivation to use biolord-classify to classify abortive cells within the scRNA-seq data at earlier time points, or in other words, identify the cells that would have progressed to become identifiably abortive at 36 hpi. We train a biolord-classify model over hepatocytes at late time points (24, 30, and 36 hpi), where an abortive population is already expected to appear 21 . As input, we use the host transcriptome along with complete supervision over spatial zone (periportal/pericentral) and time (24, 30, 36 hpi), and partial state classification (abortive/productive/unknown) (Supplementary Note 2).…”

Section: Biolord Exposes the Transient Trajectory Towards Distinct In...mentioning

confidence: 99%

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Biological representation disentanglement of single-cell data

Piran

Cohen

Hoshen

et al. 2023

Preprint

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Due to its internal state or external environment, a cell’s gene expression profile contains multiple signatures, simultaneously encoding information about its characteristics. Disentangling these factors of variations from single-cell data is needed to recover multiple layers of biological information and extract insight into the individual and collective behavior of cellular populations. While several recent methods were suggested for biological disentanglement, each has its limitations; they are either task-specific, cannot capture inherent nonlinear or interaction effects, cannot integrate layers of experimental data, or do not provide a general reconstruction procedure. We presentbiolord, a deep generative framework for disentangling known and unknown attributes in single-cell data. Biolord exposes the distinct effects of different biological processes or tissue structure on cellular gene expression. Based on that, biolord allows generating experimentally-inaccessible cell states by virtually shifting cells across time, space, and biological states. Specifically, we showcase accurate predictions of cellular responses to drug perturbations and generalization to predict responses to unseen drugs. Further, biolord disentangles spatial, temporal, and infection-related attributes and their associated gene expression signatures in a single-cell atlas ofPlasmodiuminfection progression in the mouse liver. Biolord can handle partially labeled attributes by predicting a classification for missing labels, and hence can be used to computationally extend an infected hepatocyte population identified at a late stage of the infection to earlier stages. Biolord applies to diverse biological settings, is implemented using the scvi-tools library, and is released as open-source software athttps://github.com/nitzanlab/biolord.

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“…Single-cell and spatial transcriptomics methods have been transformative in understanding placental development 34,35 , mapping the transcriptome of the parasites [36][37][38] and studying host-pathogen interactions 39,40 . Here, we optimise first-trimester placental explants and use them to study host-pathogens interactions at the single-cell level.…”

Section: Introductionmentioning

confidence: 99%

Early infection response of the first trimester human placenta at single-cell scale

Hoo

Ruiz-Morales

Kelava

et al. 2023

Preprint

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Placental infections are a major worldwide burden, particularly in developing countries. The placenta is a transient tissue located at the interface between the mother and the fetus. Some pathogens can access the placental barrier resulting in pathological transmission from mother to fetus, which may have a profound impact on the health of the developing fetus. Limited tissue accessibility, critical differences between humans and mice, and, until recently, lack of properin vitromodels, have hampered our understanding of the early placental response to pathogens. Here we use single-cell transcriptomics to describe the placental primary defence mechanisms against three pathogens that are known to cause fetal and maternal complications during pregnancy -Plasmodium falciparum,Listeria monocytogenesandToxoplasma gondii. We optimise ex vivo placental explants of the first-trimester human placenta and show that trophoblasts (the epithelial-like cells of the placenta), and Hofbauer cells (placental macrophages) orchestrate a coordinated inflammatory response after 24 hours of infection. We show that hormone biosynthesis and transport are downregulated in the trophoblasts, suggesting that protective responses are promoted at the expense of decreasing other critical functions of the placenta, such as the endocrine production and the nourishment of the fetus. In addition, we pinpoint pathogen-specific effects in some placental lineages, including a strong mitochondrial alteration in the Hofbauer cells in response toT. gondii. Finally, we identify adaptive strategies and validate nutrient acquisition employed by theP. falciparumduring placental malaria infection. This study provides the first detailed cellular map of the first-trimester placenta upon infection and describes the early events that may lead to fetal and placental disorders if left unchecked.

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A spatiotemporally resolved single-cell atlas of the Plasmodium liver stage

Cited by 33 publications

References 41 publications

Plasmodium exoerythrocytic parasites redirect trafficking of human proteins to the parasitophorous vacuole

Plasmodium exoerythrocytic parasites redirect trafficking of human proteins to the parasitophorous vacuole

Biological representation disentanglement of single-cell data

Early infection response of the first trimester human placenta at single-cell scale

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