Date of Award

Summer 8-12-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

David Artis

Second Advisor

John M. Murray

Third Advisor

E. John Wherry

Abstract

Toxoplasma gondii infection provides a clinically important, and experimentally tractable, system for exploring the delicate balance of interactions between a pathogen and its host, resulting in the long-term survival of both. Many studies have shown that this parasite is susceptible to, and can actively manipulate a variety of innate and acquired immune responses. It also known that the nature of these responses is likely to be critical in distinguishing between the development of acute disease, chronic, asymptomatic infection, and parasite clearance. However, the factors responsible for controlling these diverse outcomes are still unclear. This dissertation explores the establishment of T. gondii infection after invasion of the small intestine and the host’s cellular response to parasites at this site. Ex vivo visualization of infection in whole tissue explants using fluorescently tagged parasites and deep-imaging techniques reveals a significantly more complex process of interaction within the small intestine than previously appreciated. After crossing the intestinal epithelium to enter the lamina propria, T. gondii parasites remain confined to the area surrounding the initial site of invasion rather than rapidly disseminating to the tissues, producing spatially restricted plaques and a high mucosal burden relative to non-mucosal tissues. The host response to T. gondii plaques is similarly striking and include a massive influx of LysM+ cells into the infection plaque. In contrast, while CD11c+ dendritic cells are recruited to the infected region, they appear to be absent from the plaque itself; perhaps reflecting host efforts to control parasite replication and block dissemination, and/or parasite efforts to modulate the host response. Activation of CD8+ T cells, which are critical for the control of replicating parasites, in response to parasite-derived antigen was also examined. Transgenic T. gondii lines engineered to target the model antigen ovalbumin to various intra- and extracellular locales demonstrate that entry into the processing pathway requires extra-parasitic antigen, indicating that these antigens are processed for MHC I presentation without entry into degradative organelles. These studies provide new insights into host-pathogen interactions, helping to elucidate the means by which T. gondii parasites establish infection and how host cells respond and control parasite infection.

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