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Single-cell analysis of mosquito hemocytes identifies signatures of immune cell subtypes and cell differentiation
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Uppsala University, Sweden.
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Number of Authors: 52021 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e66192Article in journal (Refereed) Published
Abstract [en]

Mosquito immune cells, known as hemocytes, are integral to cellular and humoral responses that limit pathogen survival and mediate immune priming. However, without reliable cell markers and genetic tools, studies of mosquito immune cells have been limited to morphological observations, leaving several aspects of their biology uncharacterized. Here, we use single-cell RNA sequencing (scRNA-seq) to characterize mosquito immune cells, demonstrating an increased complexity to previously defined prohemocyte, oenocytoid, and granulocyte subtypes. Through functional assays relying on phagocytosis, phagocyte depletion, and RNA-FISH experiments, we define markers to accurately distinguish immune cell subtypes and provide evidence for immune cell maturation and differentiation. In addition, gene-silencing experiments demonstrate the importance of lozenge in defining the mosquito oenocytoid cell fate. Together, our scRNA-seq analysis provides an important foundation for future studies of mosquito immune cell biology and a valuable resource for comparative invertebrate immunology.

Place, publisher, year, edition, pages
2021. Vol. 10, article id e66192
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-197695DOI: 10.7554/eLife.66192ISI: 000687203500001PubMedID: 34318744OAI: oai:DiVA.org:su-197695DiVA, id: diva2:1603019
Available from: 2021-10-14 Created: 2021-10-14 Last updated: 2023-03-01Bibliographically approved
In thesis
1. Uncovering the genetics underlying host-parasite interactions during Plasmodium falciparum malaria transmission
Open this publication in new window or tab >>Uncovering the genetics underlying host-parasite interactions during Plasmodium falciparum malaria transmission
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In eukaryotes, cellular differentiation is often orchestrated by programmed arrays of activation and repression of genes underlying the specific phenotypes of cell-types. To complete its life cycle, the single-celled Apicomplexan parasite Plasmodium falciparum, the most deadly of the human malaria parasites, must repeatedly differentiate and convert into unique cell types that can exploit niches within their human and mosquito hosts. One of these key developmental transitions occurs in the human host and includes sexual-stage commitment, followed by gametocyte development, which results in male and female gametocytes that can infect the female anopheline mosquito once taken up during the blood meal. The following gamete stage undergoes fusion and meiosis, followed by morphological changes as they invade the midgut wall to form the oocyst. The sexual stages are responsible for malaria transmission and the spread of antimalarial resistance, making it an important target for malaria eradication. Previous studies have established the understanding of a few mechanisms involved in sexual differentiation; the transcription factor, AP2-G, is a master regulator of sexual commitment. Uncovering genes and regulators underlying P. falciparum sexual stage development, including host-parasite interactions are the subjects of this thesis. 

  In paper I, we describe the temporal landscape of differential transcriptional programs underlying the P. falciparum male and female gametocyte development and highlight a bifurcation point for the onset of differential male and female transcriptional programs. Furthermore, we predict novel candidate driver genes underlying sexual cell fate determination in P. falciparum. Finally, we traced the potential sex-specific regulatory mechanisms among the ApiAP2 family of transcription factors including prediction of target genes based on co-expression and the presence of upstream binding sites, rendering a motif-driven gene regulatory network.

  In paper II, we study the P. falciparum development in the mosquito midgut, from unfertilized female gamete through the first 20 hours of development, including the zygote and ookinete stages. Using pseudotime analysis, we demonstrate that the transcriptional trajectory of the parasite is controlled by three main transcriptional programs including five unique transcriptional stages. Further, we employ structural-based functional predictions to predict intrinsically disordered proteins encoding upregulated genes through the mid to late ookinete with antigenic properties, which may serve as suitable targets for transmission suppression strategies. 

  In paper III, we utilize single-cell RNA sequencing combined with functional assays to demonstrate an increased complexity of the Anopheles mosquito immune cells, previously defined as hemocytes, Based on panels of genetic markers and morphological traits. We define additional marker genes that enable deeper characterization of Anopheles immune cell subtypes and uncover transcriptional programs involved in immune cell differentiation and maturation.

  In summary, this thesis aims to uncover previously unknown aspects of eukaryotic cell fate determination and life cycle stage differentiation with a focus on P. falciparum sexual stage development. Furthermore, we aim to enable deeper characterization of the Anopheles mosquito immune cell subtypes, their differentiation, development, and fate during steady-state and upon immune activation.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, Stockholm University, 2023. p. 65
Keywords
Malaria, Plasmodium falciparum, Genomics, single-cell RNA-seq, Parasite cell fate, Anopheles gambiae, ApiAP2 transcription factors, driver genes, computational biology
National Category
Bioinformatics and Systems Biology Microbiology Cell Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-215063 (URN)978-91-8014-218-2 (ISBN)978-91-8014-219-9 (ISBN)
Public defence
2023-04-28, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 09:30 (English)
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Available from: 2023-04-03 Created: 2023-03-01 Last updated: 2023-03-22Bibliographically approved

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Kwon, HyeogsunMohammed, MubasherAnkarklev, JohanSmith, Ryan C.

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