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Cytoplasmic sensing of Toxoplasma gondii infection and host cell programmed necrosis

Objective

My goal is to understand how cell-autonomous immunity (CAI) can detect intracellular parasites such as Toxoplasma gondii in their membrane-bounded intracellular niches, how recognition induces necrosis of the host cell, and how host death signalling pathways contribute to inflammatory disorders. Although adaptive immunity ultimately contributes to host survival, the initial response is controlled by innate mechanisms. Mice rely primarily on IFNγ-induced CAI effectors virtually absent in humans, the immunity-related GTPases (IRGs). Parasitophorous vacuole (PV) membrane attack by IRGs results in parasite eviction and elimination, swiftly followed by regulated necrosis of the host cell. Preciously little is known about how parasite sensing drives cell death, particularly in (mouse and human) non-haematopoietic cells (NHCs) lacking the full antimicrobial arsenal of immune cells. Yet necrosis is key to limiting infection and driving parasite chronicity, while potentially eliciting immunopathology. I have 2 objectives: 1) the identification of the intracellular sensor(s) of T. gondii ligands and/or vacuole damage and 2) the dissection of the signalling pathway(s) leading to parasite/cell demise. Using a combination of genetic screens and cell biology tools, I will pinpoint PRR/necrosis genes involved. Elucidating these signalling pathways will help direct therapeutic interventions relevant for toxoplasmosis and inflammatory diseases. This proposal and accompanying career development plan, to be supervised by Prof. Jonathan C. Howard and hosted by the IGC, will be fostered by a dynamic research environment and crucial collaborations that will enable me to receive the necessary training and transferrable skills to establish my own lab. In turn, my extensive training in host-pathogen interactions will greatly benefit this project and the IGC, potentiating integration of knowledge/expertise.

Fields of science (EuroSciVoc)

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Topic(s)

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Funding Scheme

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MSCA-IF-EF-RI - RI – Reintegration panel

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2015

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Coordinator

FUNDACAO CALOUSTE GULBENKIAN
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 160 635,60
Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 160 635,60
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