Abstract
Toxoplasma gondii is an obligate intracellular protozoan parasite capable of infecting warm-blooded animals by ingestion. The organism enters host cells and resides in the cytoplasm in a membrane-bound parasitophorous vacuole (PV). Inducing an interferon response enables IFN-γ-inducible immunity-related GTPase (IRG protein) to accumulate on the PV and to restrict parasite growth. However, little is known about the mechanisms by which IRG proteins recognize and destroy T. gondii PV. We characterized the role of IRG protein Irgb6 in the cell-autonomous response against T. gondii, which involves vacuole ubiquitination and breakdown. We show that Irgb6 is capable of binding a specific phospholipid on the PV membrane. Furthermore, the absence of Irgb6 causes reduced targeting of other effector IRG proteins to the PV. This suggests that Irgb6 has a role as a pioneer in the process by which multiple IRG proteins access the PV. Irgb6-deficient mice are highly susceptible to infection by a strain of T. gondii avirulent in wild-type mice.
Highlights
Healthy mammalian hosts activate immune responses against pathogenic infections
To test whether Irgb6 is involved in IFN-γ–mediated PV membrane (PVM) disruption, we performed electron microscopy to analyze IFN-γ–stimulated wild-type and Irgb6-deficient MEFs infected with T. gondii
Soon after T. gondii invades IFN-γ–stimulated mouse cells, the parasite PVM becomes coated with multiple effector immunity-related GTPases (IRGs) proteins and is eventually disrupted (Martens et al, 2005)
Summary
Healthy mammalian hosts activate immune responses against pathogenic infections. The innate immune response first induces IL-12 production by antigen-presenting cells, such as macrophages and dendritic cells. Regulator IRG proteins can maintain effector IRG proteins in an inactive GDP-bound state, potentially preventing the latter from inappropriate activation on host cell membrane– bounded vesicular systems In their absence, effector IRG proteins likely form GTP-bound aggregates and are unable to interact with the Toxoplasma gondii parasitophorous vacuole (PV) (Martens et al, 2004; Hunn et al, 2008; Hunn & Howard, 2010; Coers, 2013; Haldar et al, 2013). GTPase activity–dependent IRG and GBP accumulation is well established as important for cellautonomous immunity to vacuolar pathogens
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