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Understanding the role of Toxoplasma gondii secreted rhoptry (ROP) and dense granule (GRA) effector proteins in host-parasite biology using reverse genetics / by Leah M. Rommereim

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Author	Rommereim, Leah M.
Title	Understanding the role of Toxoplasma gondii secreted rhoptry (ROP) and dense granule (GRA) effector proteins in host-parasite biology using reverse genetics / by Leah M. Rommereim
Date	2015
Abstract	Toxoplasma gondii is an obligate intracellular pathogen that is able to survive in a range of hosts due to its repertoire of secreted effector proteins. Utilizing the type I and type II Δku80 strains we engineered a collection of targeted knockout strains that lack a ROP or GRA protein. We determined the virulence of each strain in mice and identified type I GRA12, ROP5, ROP18 and type II ROP5 as major virulence factors. Controlling a T. gondii infection requires a strong CD8+ T cell and IFN-γ host immune response, which is activated by MHC-I antigen presentation. We engineered each of our type I knockout strains to express the model antigen ovalbumin (OVA) and tested each for their ability to modify MHC-I antigen presentation. Infection of macrophages and dendritic cells with knockout strains that lacked type I GRA2, GRA12, ROP5 or ROP18 exhibited significantly higher levels of antigen presentation than the OVA-expressing parental Δku80 strain. The ability of ROP18 to block antigen presentation was dependent on IFN- γ activation of the host cell and the expression of immunity-related GTPases (IRGs). Whereas ROP5 and GRA2 limited antigen presentation by IFN-γ and IRG-dependent and independent mechanisms and GRA12 by an IFN-γ and IRG- independent mechanism in infected host cells. These results revealed that both macrophages and dendritic cells can utilize IRGs to access antigens within the parasitophorous vacuole for class I processing and presentation. Additionally, we unexpectedly determined that the type II ROP5 is, like the type I ROP5, able to block IFN-γ activated IRG-mediated vacuole destruction. By taking a targeted reverse genetics approach to identifying and characterizing major virulence factors of T. gondii we’ve demonstrated that a main function of these secreted effector proteins is to block IRG-dependent vacuole destruction leading to MHC-I antigen presentation and subsequent CD8+ T cell response. As well, we’ve identified that many of these proteins are multi-functional in the host cell and have significant functions which have not yet been deciphered, opening up a new areas of research to determine the extent of their activity and mechanisms.
Description	1 online resource (xiv, 245 pages) : illustrations (some color)
Format	application/pdf
College	Geisel School of Medicine at Dartmouth -- Department of Microbiology and Immunology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1920

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Understanding the role of Toxoplasma gondii secreted rhoptry (ROP) and dense granule (GRA) effector proteins in host-parasite biology using reverse genetics / by Leah M. Rommereim

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