Cell death of gamma interferon-stimulated human fibroblasts upon Toxoplasma gondii infection induces early parasite egress and limits parasite replication

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Abstract

The intracellular protozoan parasite Toxoplasma gondii is a major foodborne illness and opportunistic infection for the immunosuppressed. Resistance to Toxoplasma is dependent on interferon-γ (IFNγ) activation of both hematopoietic and non-hematopoietic cells. While IFNγ-induced innate immunity in non-hematopoietic cells has been extensively studied in mice, it remains unclear what resistance mechanisms are relied on in non-hematopoietic human cells. Here, we report an IFNγ-induced mechanism of resistance to Toxoplasma in primary human foreskin fibroblasts (HFFs) that does not depend on deprivation of tryptophan or iron. Additionally, 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 IFNγ-induced cell death and early egress limits replication in HFFs and could promote clearance of the parasite by immune cells.