Campylbacter jejuni flagellar regulation and synthesis

Summary

Principal Investigator: David R Hendrixson
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2011-07-01 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. ncbi A phase-variable mechanism controlling the Campylobacter jejuni FlgR response regulator influences commensalism
    David R Hendrixson
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Mol Microbiol 61:1646-59. 2006
  2. pmc A regulatory checkpoint during flagellar biogenesis in Campylobacter jejuni initiates signal transduction to activate transcription of flagellar genes
    Joseph M Boll
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    MBio 4:e00432-13. 2013
  3. pmc Spatial and numerical regulation of flagellar biosynthesis in polarly flagellated bacteria
    Barbara I Kazmierczak
    Departments of Medicine and Microbial Pathogenesis, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520 8022, USA
    Mol Microbiol 88:655-63. 2013
  4. pmc Architecture of the major component of the type III secretion system export apparatus
    Patrizia Abrusci
    Sir William Dunn School of Pathology, Oxford University, Oxford, UK
    Nat Struct Mol Biol 20:99-104. 2013
  5. pmc EptC of Campylobacter jejuni mediates phenotypes involved in host interactions and virulence
    Thomas W Cullen
    Section of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA
    Infect Immun 81:430-40. 2013
  6. pmc Identification and analysis of flagellar coexpressed determinants (Feds) of Campylobacter jejuni involved in colonization
    Angelica M Barrero-Tobon
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9048, USA
    Mol Microbiol 84:352-69. 2012
  7. pmc Polar flagellar biosynthesis and a regulator of flagellar number influence spatial parameters of cell division in Campylobacter jejuni
    Murat Balaban
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
    PLoS Pathog 7:e1002420. 2011
  8. pmc A specificity determinant for phosphorylation in a response regulator prevents in vivo cross-talk and modification by acetyl phosphate
    Joseph M Boll
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9048, USA
    Proc Natl Acad Sci U S A 108:20160-5. 2011
  9. pmc Analysis of the LIV system of Campylobacter jejuni reveals alternative roles for LivJ and LivK in commensalism beyond branched-chain amino acid transport
    Deborah A Ribardo
    Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room NL 4 138A, Dallas, TX 75390 9048, USA
    J Bacteriol 193:6233-43. 2011
  10. ncbi Motility and chemotaxis in Campylobacter and Helicobacter
    Paphavee Lertsethtakarn
    Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, Santa Cruz, California 95064, USA
    Annu Rev Microbiol 65:389-410. 2011

Detail Information

Publications19

  1. ncbi A phase-variable mechanism controlling the Campylobacter jejuni FlgR response regulator influences commensalism
    David R Hendrixson
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Mol Microbiol 61:1646-59. 2006
    ..jejuni that is absent in other Campylobacter species and contribute to reasons why C. jejuni is more frequently found as a commensal organism in poultry and as the cause of disease in humans...
  2. pmc A regulatory checkpoint during flagellar biogenesis in Campylobacter jejuni initiates signal transduction to activate transcription of flagellar genes
    Joseph M Boll
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    MBio 4:e00432-13. 2013
    ..jejuni, this regulatory checkpoint may exist in a broad range of bacteria to influence similar TCSs and flagellar gene transcription...
  3. pmc Spatial and numerical regulation of flagellar biosynthesis in polarly flagellated bacteria
    Barbara I Kazmierczak
    Departments of Medicine and Microbial Pathogenesis, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520 8022, USA
    Mol Microbiol 88:655-63. 2013
    ..Continued examination of these proteins in polar flagellates is expected to reveal how different bacteria have adapted FlhF or FlhG with specific activities to tailor flagellar biosynthesis and motility to fit the needs of each species...
  4. pmc Architecture of the major component of the type III secretion system export apparatus
    Patrizia Abrusci
    Sir William Dunn School of Pathology, Oxford University, Oxford, UK
    Nat Struct Mol Biol 20:99-104. 2013
    ..This defines the molecular architecture of the dominant component of the export apparatus and allows us to propose a model for the molecular mechanisms controlling secretion...
  5. pmc EptC of Campylobacter jejuni mediates phenotypes involved in host interactions and virulence
    Thomas W Cullen
    Section of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA
    Infect Immun 81:430-40. 2013
    ..Our results indicate that modification of surface structures with pEtN by EptC is key to its ability to promote commensalism in an avian host and to survive in the mammalian gastrointestinal environment...
  6. pmc Identification and analysis of flagellar coexpressed determinants (Feds) of Campylobacter jejuni involved in colonization
    Angelica M Barrero-Tobon
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9048, USA
    Mol Microbiol 84:352-69. 2012
    ....
  7. pmc Polar flagellar biosynthesis and a regulator of flagellar number influence spatial parameters of cell division in Campylobacter jejuni
    Murat Balaban
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
    PLoS Pathog 7:e1002420. 2011
    ..Furthermore, we found that other polarly-flagellated bacteria produce FlhG proteins that influence cell division, suggesting that FlhG and polar flagella may function together in a broad range of bacteria to spatially regulate division...
  8. pmc A specificity determinant for phosphorylation in a response regulator prevents in vivo cross-talk and modification by acetyl phosphate
    Joseph M Boll
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9048, USA
    Proc Natl Acad Sci U S A 108:20160-5. 2011
    ..In addition to mechanisms limiting cross-talk between noncognate HKs and RRs, our work suggests that RRs can possess domains that prevent in vivo cross-talk between RRs and the endogenous metabolite AcP to ensure signaling specificity...
  9. pmc Analysis of the LIV system of Campylobacter jejuni reveals alternative roles for LivJ and LivK in commensalism beyond branched-chain amino acid transport
    Deborah A Ribardo
    Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room NL 4 138A, Dallas, TX 75390 9048, USA
    J Bacteriol 193:6233-43. 2011
    ..In contrast to other studies indicating a requirement and utilization of other specific amino acids for colonization, acquisition of branched-chain amino acids does not appear to be a determinant for C. jejuni during commensalism...
  10. ncbi Motility and chemotaxis in Campylobacter and Helicobacter
    Paphavee Lertsethtakarn
    Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, Santa Cruz, California 95064, USA
    Annu Rev Microbiol 65:389-410. 2011
    ..Chemoreceptors in these bacteria contain nonconserved ligand binding domains, with several chemoreceptors matched to environmental signals. Together, these mechanisms allow for swimming motility that is essential for colonization...
  11. pmc Structural diversity of bacterial flagellar motors
    Songye Chen
    Division of Biology, California Institute of Technology, Pasadena, CA, USA
    EMBO J 30:2972-81. 2011
    ..The combination of conserved and specially-adapted structures seen here sheds light on how this complex protein nanomachine has evolved to meet the needs of different species...
  12. pmc Change is good: variations in common biological mechanisms in the epsilonproteobacterial genera Campylobacter and Helicobacter
    Jeremy J Gilbreath
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA
    Microbiol Mol Biol Rev 75:84-132. 2011
    ....
  13. pmc Functional analysis of the RdxA and RdxB nitroreductases of Campylobacter jejuni reveals that mutations in rdxA confer metronidazole resistance
    Deborah A Ribardo
    University of Texas Southwestern Medical School, Department of Microbiology, Dallas, TX 75390 9048, USA
    J Bacteriol 192:1890-901. 2010
    ....
  14. pmc FlhF and its GTPase activity are required for distinct processes in flagellar gene regulation and biosynthesis in Campylobacter jejuni
    Murat Balaban
    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9048, USA
    J Bacteriol 191:6602-11. 2009
    ..jejuni FlhF GTPase are required for distinct steps in flagellar gene expression and biosynthesis. Our findings are likely applicable to many polarly flagellated bacteria that utilize FlhF in flagellar biosynthesis processes...
  15. pmc Activation of the Campylobacter jejuni FlgSR two-component system is linked to the flagellar export apparatus
    Stephanie N Joslin
    University of Texas Southwestern Medical School, Department of Microbiology, 5323 Harry Hines Boulevard, Dallas, TX 75390 9048, USA
    J Bacteriol 191:2656-67. 2009
    ..This study indicates that these apparatuses have broader functions beyond flagellar protein secretion, including activation of essential two-component regulatory systems required for expression of sigma(54)-dependent flagellar genes...
  16. pmc Restoration of flagellar biosynthesis by varied mutational events in Campylobacter jejuni
    David R Hendrixson
    Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA
    Mol Microbiol 70:519-36. 2008
    ..jejuni and suggests that the bacterium may possess a repertoire of mutational mechanisms to overcome genetic lesions that impair production of virulence and colonization determinants while lacking a normal mismatch repair system...
  17. pmc Analysis of the Campylobacter jejuni FlgR response regulator suggests integration of diverse mechanisms to activate an NtrC-like protein
    Stephanie N Joslin
    University of Texas Southwestern Medical School, Department of Microbiology, Dallas, TX 75390, USA
    J Bacteriol 190:2422-33. 2008
    ..Our results demonstrate that FlgR activation mechanisms are unusual among characterized NtrC-like proteins and emphasize that various means are utilized by the NtrC family of proteins to control the transcription of target genes...
  18. pmc Characterization of two putative cytochrome c peroxidases of Campylobacter jejuni involved in promoting commensal colonization of poultry
    Lacey K Bingham-Ramos
    University of Texas Southwestern Medical Center, Department of Microbiology, 5323 Harry Hines Boulevard, Dallas, TX 75390 9048, USA
    Infect Immun 76:1105-14. 2008
    ..Our data suggest that DocA and Cjj0382 have characteristics of CCPs but likely perform different physiological functions for the bacterium in colonization that are not related to resisting oxidative stress...
  19. pmc Hemerythrins in the microaerophilic bacterium Campylobacter jejuni help protect key iron-sulphur cluster enzymes from oxidative damage
    John J Kendall
    Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield, UK
    Environ Microbiol 16:1105-21. 2014
    ..We conclude that oxygen lability and poor repair of Por and Oor are major contributors to microaerophily in C. jejuni; hemerythrins help prevent enzyme damage microaerobically or during oxygen transients. ..

Research Grants30

  1. Coordination of metabolism and virulence during infection
    Tony Romeo; Fiscal Year: 2013
    ..Thus, an understanding of the conditions and stimuli affecting SirA and CsrA activities and the mechanisms by which these proteins coordinate virulence and metabolic gene expression may be applicable to a broad range of pathogens. ..
  2. Severe Enteric Disease: Pathogenesis and Response
    James B Kaper; Fiscal Year: 2013
    ....
  3. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  4. Structural Components of the Campylobacter jejuni Polar Flagellar Motor
    David R Hendrixson; Fiscal Year: 2013
    ....
  5. Oklahoma Center for Respiratory and Infectious Diseases
    Lin Liu; Fiscal Year: 2013
    ..The completion of the goals of the present COBRE will have a major impact on research programs on respiratory infectious diseases in the State of Oklahoma. ..
  6. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  7. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  8. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  9. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  10. MOLECULAR AND FUNCTIONAL ANALYSES OF THE PMRA/PMRB REGULATORY SYSTEM
    EDUARDO GROISMAN; Fiscal Year: 2013
    ..The proposed research will uncover the mechanisms that result in differential control of cell surface determinants in the pathogen Salmonella enterica and in the normal member of the human flora Escherichia coli. ..
  11. Structure and function of prokaryotic appendages by cryo-electron tomography
    Elizabeth R Wright; Fiscal Year: 2013
    ..In addition, this state of the art technology calls for the development of new software and improvement of already existing algorithms for a more efficient and biologically relevant filtering and 'denoising'of cryo-ET data. ..
  12. Spatial and Temporal Regulation of Angiogenesis
    HAROLD FISHER DVORAK; Fiscal Year: 2013
    ..abstract_text> ..
  13. Reciprocal Control of Motility and Adherence in UTI
    Harry L Mobley; Fiscal Year: 2013
    ..Understanding how these bacteria cause urinary tract infection will help us to develop antimicrobial agents and vaccines to combat these infections that each year costs the United States nearly 3 billion dollars to treat. ..