Abstract
The intracellular parasite Toxoplasma gondii resides inside a vacuole, which shields it from the host’s intracellular defense mechanisms. The cytokine interferon gamma (IFNγ) upregulates host cell effector pathways that are able to destroy the vacuole, restrict parasite growth and induce host cell death. Interferon-inducible GTPases such as the Guanylate Binding Proteins (GBPs), autophagy proteins and ubiquitin-driven mechanisms play important roles in Toxoplasma control in mice and partly also in humans. The host inflammasome is regulated by GBPs in response to bacterial infection in murine cells and may also respond to Toxoplasma infection. Elucidation of murine Toxoplasma defense mechanisms are guiding studies on human cells, while inevitably leading to the discovery of human-specific pathways that often function in a cell type-dependent manner.
Highlights
Toxoplasma gondii is an important pathogen of animals and humans with ~30% of the world’s population chronically infected
Much progress has been made toward the understanding of how the cell-autonomous defense to Toxoplasma is organized in IFNγ-stimulated murine cells
Immunity Regulated GTPases (IRGs) and Guanylate Binding Proteins (GBPs) as disruptors of the PV membrane (PVM) are at the center of Toxoplasma counter-measures with the parasitophorous vacuole (PV) initially tagged by ubiquitin
Summary
Toxoplasma gondii is an important pathogen of animals and humans with ~30% of the world’s population chronically infected. Interferon gamma (IFNγ) is the central cytokine in eliciting anti-Toxoplasma effector mechanisms These mechanisms involve either the direct destruction of the PVM, the acidification of the intravacuolar environment, the starvation of the parasite inside the vacuole or the activation of host cell death upon infection. We focus on how GBPs, autophagy and ubiquitin restrict the parasite and on how GBPs are linked to host cell death pathways to control infection in general. IRGs and GBPs collaborate in their function in mice [10,11,12] Members of both IRGs and GBPs control Toxoplasma through different mechanisms depending on host species and cell type and different Toxoplasma strains differ in their susceptibility to IRG/GBP-mediated restriction because of strain differences in effectors that counteract the IRGs/GBPs (see below and Table 1). Pyroptosis can be activated without cleavage of Caspase-1 and further experiments will have to investigate the exact mechanism of cell death
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