Post-transcriptional regulation of virulence in Campylobacter jejuni

Project: Research project

Description

ABSTRACT Campylobacter jejuni is a leading bacterial cause of gastroenteritis in the United States, and is responsible for sporadic disease as well as food-borne and water-borne outbreaks. It is also a Category B Bioterrorism Agent. There are at least 2 million cases of C. jejuni gastroenteritis each year in the U.S.;an incidence equal or greater to that of Salmonella and Shigella combined. A subset of C. jejuni infections lead to the development of Guillain-Barr Syndrome, an acute motor paralysis apparently resulting from an autoimmune response directed at C. jejuni surface antigens mimicking gangliosides. Despite the high prevalence of Campylobacter disease and more than 20 years of study, the mechanisms by which C. jejuni causes disease remain obscure. Several C. jejuni virulence factors have been identified, yet the mechanisms by which they are regulated remain largely unknown. Recently we have begun characterization of the C. jejuni ortholog of the post-transcriptional regulator CsrA. In other bacteria, CsrA mediates the regulation of numerous important virulence phenotypes, including carbon metabolism, motility, quorum sensing, biofilm production and others. CsrA activity is controlled by inducible small regulatory RNAs (sRNAs) that bind competitively to CsrA. We have constructed a C. jejuni mutant lacking csrA, and have shown that the csrA mutant exhibits pleiotropic virulence-related phenotypes including decreased motility, epithelial cell adherence, biofilm formation, and resistance to oxidative stress (including ambient air, hydrogen peroxide, and superoxide). Conversely, the csrA mutant shows increased invasion of human epithelial cells. This underscores the importance of the CsrA regulon in C. jejuni pathogenesis. Overall hypothesis: Campylobacter jejuni CsrA plays an important role in the pathogenesis of C. jejuni via the post-transcriptional regulation of virulence properties. We propose a detailed study of CsrA-mediated post-transcriptional gene regulation in C. jejuni, focusing on the mechanism by which CsrA controls the expression of virulence properties. We will use genetic, proteomic and biochemical approaches to achieve the goals outlined in these three specific aims: Aim 1) Continue characterizing the CsrA regulon and cis-acting factors required for CsrA regulation of these proteins, Aim 2) Identify and characterize the sRNA component that antagonizes CsrA activity, and Aim 3) Identify environmental conditions and regulatory proteins that control expression of csrA.
StatusFinished
Effective start/end date7/19/107/18/12

Funding

  • National Institutes of Health: $327,900.00

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Campylobacter jejuni
Virulence
Regulon
Gastroenteritis
Biofilms
Epithelial Cells
Biological Warfare Agents
RNA
Campylobacter Infections
Phenotype
Quorum Sensing
Shigella
Campylobacter
Gangliosides
Virulence Factors
Surface Antigens
Autoimmunity
Salmonella
Superoxides
Paralysis

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)