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A genome-wide loss-of-function screen identifies Toxoplasma gondii genes that determine fitness in interferon gamma-activated murine macrophages

Research output: Working paper

  • Yifan Wang
  • Lamba Omar Sangare
  • Tatiana C. Paredes-Santos
  • Shruthi Krishnamurthy
  • Musa Hassan
  • Anna M. Furuta
  • Benedikt M. Markus
  • Sebastian Lourido
  • Jeroen P.J. Saeij

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Original languageEnglish
PublisherbioRxiv, at Cold Spring Harbor Laboratory
DOIs
Publication statusPublished - 6 Dec 2019

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NamebioRxiv
PublisherbioRxiv, at Cold Spring Harbor Laboratory

Abstract

Macrophages play an essential role in the early immune response against Toxoplasma and are the cell type preferentially infected by the parasite in vivo. Interferon gamma (IFNγ) elicits a variety of anti-Toxoplasma activities in macrophages. Using a genome-wide CRISPR screen we identified ∼130 Toxoplasma genes that determine parasite fitness in naїve macrophages and ∼466 genes that determine fitness in IFNγ-stimulated murine macrophages, seven of which we investigated and confirmed. We show that one of these genes encodes dense granule protein GRA45, which contains a putative chaperone-like domain, and which we show is critical in preventing other GRA effectors from aggregating. Parasites lacking GRA45 mislocalize GRA effectors upon secretion, are more susceptible to IFNγ-mediated growth inhibition, and have reduced virulence in mice. Our results provide a resource for the community to further explore the function of Toxoplasma genes that determine fitness in IFNγ-stimulated macrophages.

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