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Zebrafish as a new model for the in vivo study of Toxoplasma gondii interaction with phagocytes

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Title: Zebrafish as a new model for the in vivo study of Toxoplasma gondii interaction with phagocytes
Authors: Yoshida, Nagisa
Item Type: Thesis or dissertation
Abstract: Toxoplasma gondii is an obligate intracellular parasite and paradigm for the study of the host immune response to infection at the cellular and molecular level. The zebrafish larva is a well-established model for the study of bacterial, viral and fungal infections in vivo. In this thesis, I use the zebrafish larva to set up a novel in vivo infection model for Toxoplasma. I use this model to explore innate leukocyte dynamics and function, and investigate the cell-intrinsic immune response to Toxoplasma infection. I also develop new tools for the in-depth study of cell-intrinsic mechanisms involved in parasite restriction. Recent studies have revealed fundamental differences in the innate host response to Toxoplasma infection between human and mice suggesting that another animal model could provide new insights into Toxoplasma control. In Chapter 1, I develop a zebrafish larval model to study Toxoplasma infection in vivo. Macrophages and neutrophils make up the cellular innate immune response, and are the first cells to respond to pathogen invasion. Studies using mice have shown that both macrophages and neutrophils are crucial for the in vivo control of Toxoplasma. However, different reports suggest that Toxoplasma can exploit macrophage and / or neutrophil biology to promote their survival. In Chapter 2, I use the Toxoplasma-zebrafish infection model developed in Chapter 1 to reveal that macrophages significantly contribute to Toxoplasma clearance in vivo. Moreover, I test for strain-specific differences in establishing infection, and show that type II and III strains establish a higher parasite burden than type I strains in vivo. Guanylate binding proteins (GBPs) are important mediators of IFN-γ-induced cell-intrinsic restriction of Toxoplasma. GBPs have been implicated in multiple cell-intrinsic pathways, including host cell death. Recent developments have highlighted key differences in GBP-mediated immunity between the human and mouse and how human GBPs restrict Toxoplasma remains poorly understood. In Chapter 3, I discover that macrophages induce host cell death to promote parasite clearance, and also reveal parasite restriction occurs independently of host cell death. Finally, I generated a zebrafish GBP2 knockout line by CRISPR/Cas to explore the role of GBPs in cell-intrinsic Toxoplasma control. Overall, the findings in this thesis highlight zebrafish larva as a useful model for the study of Toxoplasma infection. I use this model to reveal important roles for macrophages in Toxoplasma clearance in vivo.
Content Version: Open Access
Issue Date: Dec-2019
Date Awarded: Jun-2020
URI: http://hdl.handle.net/10044/1/97983
DOI: https://doi.org/10.25560/97983
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Mostowy, Serge
Frickel, Eva
Sponsor/Funder: Francis Crick Institute
Imperial College London
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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