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- W60871245 abstract "Toxoplasma gondii is a widespread protozoan parasite infecting all warm-blooded animals and causing disease in immunocompromised individuals and in utero. The pathogen depends on the intracellular life style residing in a specialized organelle, termed parasitophorous vacuole (PV), in order to survive and replicate. Cell-autonomous immunity, regulated by IFNg, is essential to restrict growth of the parasite in mouse and man. In mouse cells, resistance to T. gondii is mediated by the family of IFN-inducible IRG proteins (p47 GTPases). Upon infection several IRG proteins associate with the PV and participate in vesiculation of the PV membrane leading to demise of the parasite and necrotic death of the cell. Until now, despite intrinsic interest, the phenomenon of IRG protein loading onto PV has not been well studied. In human cells, depletion of cellular tryptophan by IDO has been reported as the major mechanism of restriction of T. gondii proliferation exerted by IFNg. IDO-independent restriction of T. gondii growth has been reported but not followed up. The process of IRG protein association with T. gondii vacuoles emerged as a rapid, organized and diffusion-driven event where multiple resistance proteins sequentially bind to the vacuolar membrane forming homomeric and heteromeric complexes. The efficient loading process requires the autophagy factor Atg5 regulating correct localisation of IRG proteins prior to infection. Virulent strains of T. gondii inhibit IRG protein association with PVs independently of individual virulence determinants ROP5, ROP16 and ROP18. Impaired loading of IRG proteins onto T. gondii vacuoles leads to reduced elimination of the parasite in IFNg-stimulated cells, underlining the importance of the phenomenon in cell-autonomous immunity to T. gondii. This study shows that density of cultured cells is the key factor in determining the mode of T. gondii control in primary human cells. IFNg-induced, proliferating cells control parasite replication independently of IDO. Consistent with absence of the IRG system in humans, the vacuolar membrane and enclosed parasite remain intact in IFNg-induced human cells. However, similar to mouse cells, human cells die by necrosis, when infected with T. gondii and stimulated with IFNg. This may not only suppress parasite growth but also amplify an antimicrobial response due to release of the proinflammatory �danger� signal HMGB1. Programmed necrosis could be efficiently suppressed at high densities of primary cells and in HeLa cell line, and tryptophan depletion becomes the main source of T. gondii control." @default.
- W60871245 created "2016-06-24" @default.
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- W60871245 date "2010-01-01" @default.
- W60871245 modified "2023-09-27" @default.
- W60871245 title "Mechanisms of Cell-autonomous Resistance to Toxoplasma gondii in Mouse and Man" @default.
- W60871245 hasPublicationYear "2010" @default.
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