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Regulation of virulence in Salmonella enterica

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Title: Regulation of virulence in Salmonella enterica
Author(s): Golubeva, Yekaterina
Director of Research: Slauch, James M.
Doctoral Committee Chair(s): Slauch, James M.
Doctoral Committee Member(s): Imlay, James A.; Metcalf, William W.; Salyers, Abigail A.
Department / Program: Microbiology
Discipline: Microbiology
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): Salmonella regulation of invasion genes superoxide survival in macrophages
Abstract: Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen, capable of causing disease in a variety of animal hosts. Both invasion of the host intestinal epithelial cells, and survival and replication in host macrophages are required for the successful establishment of the typhoid-like infection in mice. Material in this thesis describes regulation of Salmonella virulence genes involved in both invasion and the systemic stages of infection. Salmonella uses the Salmonella Pathogenicity Island I (SPI1) Type Three Secretion System (T3SS) to invade intestinal epithelia in the distal ileum of the host small intestine. HilA, a master regulator of the system, determines the level of SPI1 T3SS in the cell. Three AraC-like regulators, HilD, HilC, and RtsA, directly activate hilA expression, as well as each other and themselves, forming a complex feed-forward regulatory loop to control SPI1 expression. The production of the SPI1 T3SS system is tightly controlled, with many regulators and environmental conditions known to affect hilA expression. We provide a classification of these various regulatory signals based on their point of integration into the SPI1 regulatory circuit showing that the SPI1 system is controlled at multiple levels. The majority of the SPI1 regulatory input integrates into the system via HilD. Regulatory signals of Class I, II, and V affect hilA expression via HilD by acting at the level of HilD protein, controlling hilD expression post-transcriptionally, or affecting HilD autoactivation, respectively. The regulatory signals in Class III control hilA independently of HilD, HilC, or RtsA, while those in Class IV affect all promoters in the SPI1 regulatory circuit. The flagellar protein FliZ is a Class I regulator of SPI1 that activates hilA expression by affecting HilD protein activity. Thus, FliZ serves as a link between flagellar regulon and SPI1. We provide evidence that the FliZ-dependent regulatory input into SPI1 is limited, despite the fact that the SPI1 and flagellar genes are co-regulated under a variety of conditions and FliZ was shown to be an important regulator of SPI1 in the mouse model of infection. In the small intestine of the host, bacteria have to respond to multiple environmental cues. Additional data suggest that the availability of inorganic phosphate can serve as a potential clue to intestinal localization and SPI1 induction in Salmonella, a phenomenon that was not previously appreciated. In the systemic stage of infection, bacteria replicating in host macrophages must survive the phagocytic respiratory burst that produces superoxide. Salmonella Typhimurium strain 14028 produces two periplasmic superoxide dismutases, SodCI and SodCII, but only SodCI contributes to virulence. Although we have shown that this is primarily due to differences in the two proteins, evidence suggested that the two genes are differentially regulated. Part of this thesis describes sodCI and sodCII regulation in vitro and in vivo. In vitro, sodCII is controlled by the RpoS sigma factor, similarly to the Escherichia coli ortholog, sodC. In contrast, sodCI is regulated by the PhoPQ two-component regulatory system, which is known to control a number of virulence genes required for survival in macrophages. Expression of sodCI is induced 10-15 fold when bacteria replicate in murine tissue culture macrophages, or in mice. This induction in macrophages is controlled by the PhoPQ system, allowing for the timely induction of sodCI within the host to combat phagocytic superoxide.
Issue Date: 2011-01-21
URI: http://hdl.handle.net/2142/18561
Rights Information: Copyright 2010 Yekaterina Golubeva
Date Available in IDEALS: 2011-01-21
2013-01-22
Date Deposited: 2010-12
 

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