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Title: Immune-mediated control of Toxoplasma gondii by a GBP1-TRIM21 complex
Author: Foltz, C. C.
ISNI:       0000 0004 8503 2975
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Infection with the parasite Toxoplasma gondii causes foetal abnormalities during pregnancy and encephalitis in immunocompromised individualsin both developed and developing countries. Inside the host cell, Toxoplasma resides in a protective parasitophorous vacuole (PV), allowing it to survive and replicate. Following infection, the cytokine interferon gamma (IFNγ) upregulates the p47 immunity-related GTPases (IRGs) and the p65 guanylate-binding proteins (GBPs). Both IRGs and GBPs are highly expressed in IFNγ-induced cells in vitro and accumulate at the PV of avirulent type II and III, but not virulent type I strains of Toxoplasma, mediating the disruption of the avirulent PV. Autophagy, the process targeting intracellular cargo for degradation by the lysosome, has been shown to be a key player in cell-autonomous resistance to Toxoplasma. Inflammasomes, the signalling platforms of the innate immunity detecting pathogenic and danger molecules, have been reported to regulate non-cell-autonomous restriction of Toxoplasma. However, the mechanisms involved in these two defence responses and what happens once the vacuole is disrupted remain unclear. In this work, I investigate the role of ubiquitin in IFNγ-dependent resistance against Toxoplasma infection. I identified the E3 ubiquitin ligase TRIM21 as a novel interaction partner of GBP1. TRIM21 and GBP1 were co-recruited to the PV of avirulent but not virulent Toxoplasma. I show that avirulent, but not virulent Toxoplasma, is ubiquitinated in an IFNγ- and TRIM21-dependent manner, with TRIM21 partly mediating Lys63 ubiquitin linkages. TRIM21 differentially regulated the transcriptional and protein levels of GBP1 and GBP2, which were identified as substrates of the E3 ligase. TRIM21 also substantially upregulated the biosynthesis of 8 cholesterol, for which Toxoplasma is auxotroph. TRIM21-/- mice were highly susceptible to Toxoplasma infection and exhibited decreased levels of proinflammatory cytokines in their serum associated with higher parasite burden in the periphery and later in the brain. These findings suggest TRIM21 is a crucial, novel restriction factor during acute Toxoplasma infection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available