Campylobacter jejuni is a leading cause of gastroenteritis in humans in the United States and in other countries throughout the world. According to the Centers for Disease Control, C. jejuni competes with Salmonella species as the leading cause of bacterial gastroenteritis in the United States. In contrast, C. jejuni is a common commensal organism of the gastrointestinal tracts of wild and agriculturally-important animals, which contributes to the large amount of C. jejuni found in the human food supply leading to sporadic cases of disease. Flagellar motility is the only proven virulence and colonization factor of C. jejuni, required to promote infection of humans and avian species for the development of disease or commensalism. C. jejuni produces a single flagellum at one or both poles of the bacterium. Thus, C. jejuni belongs to a significant group of bacterial pathogens, such as Vibrio, Pseudomonas, and Helicobacter species, that are programmed to produce a limited number of flagella and place these organelles only at the poles, unlike more commonly studied peritrichous bacteria such as E. coli and Salmonella species. We have used C. jejuni as a model system to understand regulation of flagellar gene expression and biosynthesis in polarly-flagellated bacterial pathogens. This regulatory system requires the flagellar export apparatus, the FlgSR two-component system and the FlhF GTPase for expression C54-dependent flagellar genes. In addition, FlhF and the putative ATP- binding protein, FlhG, are required for proper flagellar placement, number, or biosynthesis with FlhG possessing an additional function in septation. The objectives of this proposal are to analyze signaling processes in C. jejuni that mediate proper expression of flagellar genes while using the flagellar regulatory system to promote a deeper understanding into the cellular biology of signaling networks, complex organelle development, and bacterial septation.
In Aim 1, we will analyze a novel signaling mechanism occurring between the flagellar export apparatus and the FlgS sensor kinase that leads to activation of the FlgSR system.
In Aim 2, we will analyze the biology of FlgR, an NtrC-like protein, which contains a unique C- terminus that allows for a likely alternative mechanism of signal transduction and transcriptional initiation.
In Aim 3, we will analyze how FlhF influences flagellar gene expression and biosynthesis and the dual functions of FlhG in controlling polar flagellar number and septation. Accomplishment of these aims will aid in understanding: 1) a unique molecular mechanism of signaling between protein systems in bacteria;2) alternative mechanisms of transcriptional initiation for an NtrC-like protein;3) how signaling networks in bacteria are insulated from each other to mediate specificity of signaling;4) complex organelle development;and 5) aspects of bacterial septation.

Public Health Relevance

Campylobacter jejuni produces a flagellum that is required for motility, infection of humans to promote diarrheal disease, and infection of animals to promote colonization. The proposed research will examine how regulatory proteins of C. jejuni function together to control production of flagella and influence other aspects of cellular biology such as bacterial division. By accomplishing research proposed in this work, we may reveal new steps in the production of virulence and colonization factors required by bacteria to promote infection that could be targeted for inactivation by therapeutics.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI065539-09
Application #
8692630
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Ranallo, Ryan
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Kendall, John J; Barrero-Tobon, Angelica M; Hendrixson, David R et al. (2014) Hemerythrins in the microaerophilic bacterium Campylobacter jejuni help protect key iron-sulphur cluster enzymes from oxidative damage. Environ Microbiol 16:1105-21
Abrusci, Patrizia; Vergara-Irigaray, Marta; Johnson, Steven et al. (2013) Architecture of the major component of the type III secretion system export apparatus. Nat Struct Mol Biol 20:99-104
Boll, Joseph M; Hendrixson, David R (2013) A regulatory checkpoint during flagellar biogenesis in Campylobacter jejuni initiates signal transduction to activate transcription of flagellar genes. MBio 4:e00432-13
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Kazmierczak, Barbara I; Hendrixson, David R (2013) Spatial and numerical regulation of flagellar biosynthesis in polarly flagellated bacteria. Mol Microbiol 88:655-63
Barrero-Tobon, Angelica M; Hendrixson, David R (2012) Identification and analysis of flagellar coexpressed determinants (Feds) of Campylobacter jejuni involved in colonization. Mol Microbiol 84:352-69
Boll, Joseph M; Hendrixson, David R (2011) A specificity determinant for phosphorylation in a response regulator prevents in vivo cross-talk and modification by acetyl phosphate. Proc Natl Acad Sci U S A 108:20160-5
Lertsethtakarn, Paphavee; Ottemann, Karen M; Hendrixson, David R (2011) Motility and chemotaxis in Campylobacter and Helicobacter . Annu Rev Microbiol 65:389-410
Balaban, Murat; Hendrixson, David R (2011) Polar flagellar biosynthesis and a regulator of flagellar number influence spatial parameters of cell division in Campylobacter jejuni. PLoS Pathog 7:e1002420

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