title: Cell death of gamma interferon-stimulated human fibroblasts upon Toxoplasma gondii infection induces early parasite egress and limits parasite replication.
abstract: The intracellular protozoan parasite Toxoplasma gondii is a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance to Toxoplasma is dependent on gamma interferon (IFN-γ) activation of both hematopoietic and nonhematopoietic cells. Although IFN-γ-induced innate immunity in nonhematopoietic cells has been extensively studied in mice, it remains unclear what resistance mechanisms are relied on in nonhematopoietic human cells. Here, we report an IFN-γ-induced mechanism of resistance to Toxoplasma in primary human foreskin fibroblasts (HFFs) that does not depend on the deprivation of tryptophan or iron. In addition, infection is still controlled in HFFs deficient in the p65 guanylate binding proteins GBP1 or GBP2 and the autophagic protein ATG5. Resistance is coincident with host cell death that is not dependent on the necroptosis mediator RIPK3 or caspases and is correlated with early egress of the parasite before replication. This IFN-γ-induced cell death and early egress limits replication in HFFs and could promote clearance of the parasite by immune cells.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Niedelman
authors.forename: Joris K
authors.initials: JK
authors.lastname: Sprokholt
authors.forename: Barbara
authors.initials: B
authors.lastname: Clough
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Frickel
authors.forename: Jeroen P J
authors.initials: JP
authors.lastname: Saeij
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D002478:Cells, Cultured; D005347:Fibroblasts; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007501:Iron; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*; D014364:Tryptophan
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C490287:GBP1 protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D007371:Interferon-gamma; D014364:Tryptophan; D007501:Iron; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C534329:GBP2 protein, human; D019204:GTP-Binding Proteins
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