Date of Award:

12-2018

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Chemistry and Biochemistry

Committee Chair(s)

Nicholas E. Dickenson

Committee

Nicholas E. Dickenson

Committee

Joan M. Hevel

Committee

Tim Gilbertson

Committee

Sean Johnson

Committee

Stephen E. Bialkowski

Abstract

Shigella are bacteria that are responsible for millions of infections and hundreds of thousands of deaths every year. The emergence of antibiotic resistant Shigella adds to the potentially devastating effect that these bacteria can have on human health. Shigella flexneri utilize specialized molecular machinery called the Type III secretion system to infect humans and cause disease. Research of this machinery promises to provide the knowledge, tools, and direction for the development of new avenues to combat shigellosis. This dissertation presents studies of two Shigella proteins, invasion plasmid antigens C and D (IpaC and IpaD). These proteins are part of a syringe and needle like protein structure that allows Shigella to secrete proteins directly into the host that hijack host cells to benefit support Shigella infections. IpaC and IpaD are part of a protein tip complex that is directly involved in these Shigella-host (e.g. human) interactions. We have advanced the biochemical tools for the in vitro study of IpaC by utilizing a new way to isolate it. This purification methodology allowed us to look at one of IpaC’s main roles, to interact with the host cell membranes. We examined IpaC’s role and tried to identify the parts of IpaC responsible for some specific interactions. We found that the parts of IpaC we believed were responsible were not but that the composition of the membrane IpaC is interacting with is more important than we previously believed. Finally, we examined a rare part of IpaD structure to determine its role. We determined that this rare feature is required for IpaD to sense Shigella’s host environment and prepare the bacteria to infect, making a promising target for anti-infective treatments against Shigella infections. Our findings advance the understanding of key molecular mechanisms that are required for Shigella virulence. We expect that our findings will aid future researchers as the pursuit for new treatments for shigellosis continues.

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