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

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

doi:10.1038/s41467-020-18991-8

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

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

Royal (Dick) School of Veterinary Studies

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 353 Toxoplasma genes that determine parasite fitness in naїve or IFNγ-activated murine macrophages, seven of which we investigated and 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 identified and characterized an important chaperone-like GRA in Toxoplasma and provided a resource for the community to further explore the function of Toxoplasma genes that determine fitness in IFNγ- activated macrophages.

Original language	English
Article number	5258 (2020)
Journal	Nature Communications
Volume	11
Early online date	16 Oct 2020
DOIs	https://doi.org/10.1038/s41467-020-18991-8
Publication status	E-pub ahead of print - 16 Oct 2020

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Musa Hassan
- Royal (Dick) School of Veterinary Studies - Group Leader
Person: Academic: Research Active

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Wang, Y., Sangare, L. O., Paredes-Santos, T. C., Hassan, M., Krishnamurthy, S., Furuta, A. M., Markus, B. M., Lourido, S., & Saeij, J. P. J. (2020). Genome-wide screens identify Toxoplasma gondii determinants of parasite fitness in IFNγ-activated murine macrophages. Nature Communications, 11, Article 5258 (2020). Advance online publication. https://doi.org/10.1038/s41467-020-18991-8

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

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 353 Toxoplasma genes that determine parasite fitness in naїve or IFNγ-activated murine macrophages, seven of which we investigated and 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 identified and characterized an important chaperone-like GRA in Toxoplasma and provided a resource for the community to further explore the function of Toxoplasma genes that determine fitness in IFNγ- activated macrophages.",

author = "Yifan Wang and Sangare, {Lamba Omar} and Paredes-Santos, {Tatiana C.} and Musa Hassan and Shruthi Krishnamurthy and Furuta, {Anna M.} and Markus, {Benedikt M.} and Sebastian Lourido and Saeij, {Jeroen P.J.}",

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AU - Wang, Yifan

AU - Sangare, Lamba Omar

AU - Paredes-Santos, Tatiana C.

AU - Hassan, Musa

AU - Krishnamurthy, Shruthi

AU - Furuta, Anna M.

AU - Markus, Benedikt M.

AU - Lourido, Sebastian

AU - Saeij, Jeroen P.J.

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N2 - 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 353 Toxoplasma genes that determine parasite fitness in naїve or IFNγ-activated murine macrophages, seven of which we investigated and 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 identified and characterized an important chaperone-like GRA in Toxoplasma and provided a resource for the community to further explore the function of Toxoplasma genes that determine fitness in IFNγ- activated macrophages.

AB - 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 353 Toxoplasma genes that determine parasite fitness in naїve or IFNγ-activated murine macrophages, seven of which we investigated and 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 identified and characterized an important chaperone-like GRA in Toxoplasma and provided a resource for the community to further explore the function of Toxoplasma genes that determine fitness in IFNγ- activated macrophages.

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DO - 10.1038/s41467-020-18991-8

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VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 5258 (2020)

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

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Musa Hassan

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