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Type: Thesis
Title: The role of wzz genes in Salmonella typhimurium virulence.
Author: Murray, Gerald Laurence
Issue Date: 2005
School/Discipline: School of Molecular and Biomedical Science : Microbiology and Immunology
Abstract: Salmonella is a genus of Gram-negative bacteria responsible for food-borne enteritis and systemic fever. Salmonellosis continues to be a serious health burden worldwide. Lipopolysaccharide (LPS) is the dominant lipid component of the outer membrane of Salmonella. LPS is composed of lipid A, an oligosaccharide core, and a polymer of O units known as O antigen. Wzz proteins control the length of O antigen by an unknown mechanism. While O antigen is essential for S. typhimurium virulence, the significance of length regulation by Wzz is not known. This study investigates the pathogenic relevance of the wzz genes in S. typhimurium. In addition to the previously recognised wzz gene (WZZ[subscript]ST), a second gene with this function (WZZ[subscript]fepE) was identified in the S. typhimurium genome. Whereas WZZ[subscript]ST specifies the production of long LPS chains with a modal length of 16-35 O antigen repeat units, WZZ[subscript]fepE conferred very long chains containing> 100 O antigen repeat units. Strains carrying mutations in one or both wzz genes were constructed to investigate the role of wzz genes in virulence. It was found that wzz-controlled regulation of O antigen length was essential for resistance to the bactericidal activity of serum complement, while studies in the mouse model of infection found that wzz genes are essential for full virulence. The wzz double mutant was complemented with heterologous wzz genes from a variety of bacterial sources. Despite variable sequence similarity of the encoded Wzz proteins each was functional in the S. typhimurium host, generating a panel of isogenic O antigen length variants. This panel of variants was used to define a minimum length requirement for complement resistance and identified relationships between O antigen length and complement consumption. Finally, the regulation of O antigen chain length was investigated. It was found that growth either in iron limiting conditions or in serum caused an increased production of LPS with very long O antigen chains (conferred by WZZ[subscript]fepE), resulting in increased complement resistance. The constitutive activation mutation of the phoPQ regulator (Phop) results in an altered O antigen distribution phenotype consistent with down-regulation of wzz genes. However PhoPQ had no effect on production of Wzz[subscript]sT as determined by immunoblotting with an antiWZZ[subscript]ST antiserum.
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2005
Keywords: wzz genes; Salmonella; lipid; antigen
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