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Vibrio cholerae pathogenesis: molecular mechanisms of colonization.

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Call No.	QR201.C5 K57 2003
Author	Kirn, Thomas Joseph, Jr.
Title	Vibrio cholerae pathogenesis: molecular mechanisms of colonization.
Date	2003
Abstract	Vibrio cholerae is a gram-negative bacterial pathogen that causes the severe diarrheal disease cholera. Several bacterial factors have been identified that are critical for V. cholerae intestinal colonization. The best characterized of these proteins is the type IV toxin coregulated pilus (TCP). The TCP structure is assembled by the products of the tcp operon genes as a polymer of repeating subunits of TcpA pilin that form long fibers which laterally associate into bundles. We have used site-directed mutagenesis to determine the molecular mechanism by which TCP mediates intestinal colonization. In vitro and in vivo analyses of the tcpA mutants reveal that a major function of TCP is to mediate bacterial interaction through direct pilus-pilus contact required for microcolony formation and productive intestinal colonization. In an effort to elucidate the functions of proteins involved in TCP biogenesis, in-frame deletions of the 10 tcp operon genes coding for putative pilus biogenesis proteins were constructed and the resulting mutants characterized with respect to the assembly and function of TCP. As a result of this analysis, we identified the product of one of these genes, tcpF, as a novel secreted colonization factor. Chromosomal deletion of tcpF yields a mutant that retains in vitro phenotypes associated with the assembly of functional TCP yet is severely attenuated for colonization of the infant mouse intestine. Furthermore, we have determined that the mechanism by which TcpF is translocated across the bacterial outer membrane requires TCP biogenesis. These results suggest a dual role for the TCP biogenesis apparatus in V. cholerae pathogenesis and a novel mechanism of intestinal colonization mediated by a soluble factor. Since a major role for TCP is bacterial interactions we established a screen to seek additional colonization factors that mediate association directly with the intestinal epithelium. This resulted in the identification of a protein (GbpA) required for efficient intestinal colonization that mediates attachment to human epithelial cells by binding N-acetylglucosamine residues present on the surface of these cells. We have demonstrated that this same protein is important for attachment to zooplankton, suggesting a role for a single protein in both the environment and the human host.
Description	1 online resource (xiv, 312 leaves) : illustrations (some color)
Format	application/pdf
Advisor	Ronald K. Taylor
Subject	Vibrio cholerae -- Molecular genetics. ; Bacteria -- Adhesion. ; Virulence (Microbiology). ; Cholera -- Pathogenesis. ; Pili (Microbiology).
College	Dartmouth Medical School -- Department of Microbiology and Immunology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	In Copyright. This material is protected by copyright and/or related rights. You are free to use this material in any way that is permitted by copyright law that applies to your use. For other uses, you need to obtain permission from the rights-holder(s). http://rightsstatements.org/page/InC/1.0/
DOI	https://doi.org/10.1349/ddlp.2777

Title	kirn2003 ocr-reduced-001 1
Full Text	Vibrio cholerae Pathogenesis: Molecular Mechanisms of Colonization A Thesis submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy m Microbiology and Immunology by Thomas Joseph Kirn Jr. DARTMOUTH COLLEGE Hanover, New Hampshire May 14, 2003

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Vibrio cholerae pathogenesis: molecular mechanisms of colonization.

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