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In Vivo CRISPR Screen Identifies TgWIP as a Toxoplasma Modulator of Dendritic Cell Migration
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-3388-061X
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2019 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 26, no 4, p. 478-492Article in journal (Refereed) Published
Abstract [en]

Toxoplasma can reach distant organs, especially the brain, leading to a lifelong chronic phase. However, genes involved in related in vivo processes are currently unknown. Here, we use focused CRISPR libraries to identify Toxoplasma genes that affect in vivo fitness. We focus on TgWIP, whose deletion affects Toxoplasmadissemination to distant organs. We show that TgWIP is secreted into the host cell upon invasion and interacts with the host WAVE regulatory complex and SHP2 phosphatase, both of which regulate actin dynamics. TgWIP affects the morphology of dendritic cells and mediates the dissolution of podosomes, which dendritic cells use to adhere to extracellular matrix. TgWIP enhances the motility and transmigration of parasitized dendritic cells, likely explaining its effect on in vivofitness. Our results provide a framework for systemic identification of Toxoplasmagenes with in vivo effects at the site of infection or on dissemination to distant organs, including the brain.

Place, publisher, year, edition, pages
2019. Vol. 26, no 4, p. 478-492
Keywords [en]
loss-of-function screen, Toxoplasma gondii, dendritic cell motility, migration, actin, WAVE complex, dissemination, virulence, CRISPR, cyst
National Category
Microbiology Cell and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
URN: urn:nbn:se:su:diva-175482DOI: 10.1016/j.chom.2019.09.008ISI: 000489300700007OAI: oai:DiVA.org:su-175482DiVA, id: diva2:1366560
Available from: 2019-10-29 Created: 2019-10-29 Last updated: 2019-11-11Bibliographically approved

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Ólafsson, Einar B.Barragan, Antonio
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Department of Molecular Biosciences, The Wenner-Gren Institute
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