Genome-wide screens identify Toxoplasma gondii determinants of parasite fitness in IFNγ-activated murine macrophages

Yifan Wang, Lamba Omar Sangaré, Tatiana C. Paredes-Santos, Musa A. Hassan, Shruthi Krishnamurthy, Anna M. Furuta, Benedikt M. Markus, Sebastian Lourido and Jeroen P. J. Saeij ()
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Yifan Wang: University of California, Davis
Lamba Omar Sangaré: University of California, Davis
Tatiana C. Paredes-Santos: University of California, Davis
Musa A. Hassan: The University of Edinburgh
Shruthi Krishnamurthy: University of California, Davis
Anna M. Furuta: University of California, Davis
Benedikt M. Markus: Whitehead Institute for Biomedical Research
Sebastian Lourido: Whitehead Institute for Biomedical Research
Jeroen P. J. Saeij: University of California, Davis

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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 identify 353 Toxoplasma genes that determine parasite fitness in naїve or IFNγ-activated murine macrophages, seven of which are further confirmed. We show that one of these genes encodes dense granule protein GRA45, which has a chaperone-like domain, is critical for correct localization of GRAs into the PVM and secretion of GRA effectors into the host cytoplasm. Parasites lacking GRA45 are more susceptible to IFNγ-mediated growth inhibition and have reduced virulence in mice. Together, we identify and characterize an important chaperone-like GRA in Toxoplasma and provide a resource for the community to further explore the function of Toxoplasma genes that determine fitness in IFNγ-activated macrophages.

Date: 2020
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DOI: 10.1038/s41467-020-18991-8

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