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Dense granule biogenesis, secretion, and function in Toxoplasma gondii.

ABSTRACT: Toxoplasma gondii is an obligate intracellular parasite and the causative agent of Toxoplasmosis. A key to understanding and treating the disease lies with determining how the parasite can survive and replicate within cells of its host. Proteins released from specialized secretory vesicles, named the dense granules (DGs), have diverse functions that are critical for adapting the intracellular environment, and are thus key to survival and pathogenicity. In this review, we describe the current understanding and outstanding questions regarding dense granule biogenesis, trafficking, and regulation of secretion. In addition, we provide an overview of dense granule protein ("GRA") function upon secretion, with a focus on proteins that have recently been identified.

SUBMITTER: Griffith MB

PROVIDER: S-EPMC9482668 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Dense granule biogenesis, secretion, and function in Toxoplasma gondii.

Griffith Michael B MB Pearce Camille S CS Heaslip Aoife T AT

The Journal of eukaryotic microbiology 20220401 6

Toxoplasma gondii is an obligate intracellular parasite and the causative agent of Toxoplasmosis. A key to understanding and treating the disease lies with determining how the parasite can survive and replicate within cells of its host. Proteins released from specialized secretory vesicles, named the dense granules (DGs), have diverse functions that are critical for adapting the intracellular environment, and are thus key to survival and pathogenicity. In this review, we describe the current und ...[more]

PMID: 35302693

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Project description:Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8+ T cells. Deletion of parasitophorous vacuole membrane (PVM) associated proteins ROP5, ROP17, ROP18, ROP35 or ROP38, intravacuolar network associated dense granule proteins GRA2 or GRA12, and GRA24 which traffics past the PVM to the host cell nucleus severely abrogated the antitumor response. In contrast, deletion of other secreted effector molecules such as GRA15, GRA16, or ROP16 that manipulate host cell signaling and transcriptional pathways, or deletion of PVM associated ROP21 or GRA3 molecules did not affect the antitumor activity. Association of ROP18 with the PVM was found to be essential for the development of the antitumor responses. Surprisingly, the ROP18 kinase activity required for resistance to IFN-γ activated host innate immunity related GTPases and virulence was not essential for the antitumor response. These data show that PVM functions of parasite secreted effector molecules, including ROP18, manipulate host cell responses through ROP18 kinase virulence independent mechanisms to activate potent antitumor responses. Our results demonstrate that PVM associated rhoptry effector proteins secreted prior to host cell invasion and dense granule effector proteins localized to the intravacuolar network and host nucleus that are secreted after host cell invasion coordinately control the development of host immune responses that provide effective antitumor immunity against established ovarian cancer.

Dataset Information

Dense granule biogenesis, secretion, and function in Toxoplasma gondii.

Publications

Dense granule biogenesis, secretion, and function in Toxoplasma gondii.

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