Characterizing the role of type IV-secreted CpeD and CpeE in Coxiella burnetii in

Summary

Principal Investigator: Daniel E Voth
Abstract: DESCRIPTION (provided by applicant): Coxiella burnetii is an intracellular bacterial pathogen and the etiologic agent of human Q fever, an acute debilitating flu-like illness that can progress to chronic endocarditis. Since its discovery over 70 years ago, mechanisms used by the pathogen to parasitize host cells remain poorly understood. During infection, C. burnetii actively regulates multiple host processes, including vesicular trafficking and cell survival. The bacterial proteins mediating these events are not known but are likely delivered to the host cytosol by a Dot/Icm type IV secretion system. The current application is designed to functionally characterize C. burnetii plasmid-encoded Dot/Icm substrates and define their role in virulence. All C. burnetii isolates either harbor a large cryptic plasmid or have plasmid sequences integrated into their chromosome, suggesting these molecules are critical for pathogen biology. Interestingly, we have identified six Dot/Icm substrates encoded by C. burnetii plasmid genes that are termed Coxiella plasmid effectors A - F (CpeA - F). Three of these proteins are conserved in all isolates and three are specific to the QpH1 plasmid from a human acute disease isolate. Aim 1 is designed to characterize the interaction of conserved CpeB and CpeD with autophagosomes and secretory organelles, respectively. Aim 2 will define requirements of all six plasmid effectors during infection. Additionally, this aim will identify effector binding host proteins and determine the requirement of these components for C. burnetii infection. Aim 3 will determine the requirement of the C. burnetii plasmid for pathogen virulence in both cell culture and a guinea pig infection model of Q fever. Collectively, the aims in the current application will provide needed insight into the mechanisms used by C. burnetii to efficiently parasitize host cells. These studies will also provide novel information regarding the role of the C. burnetii cryptic plasmid in pathogen virulence. PUBLIC HEALTH RELEVANCE: Coxiella burnetii is an intracellular bacterial pathogen that causes the zoonosis human Q fever, a debilitating acute disease that also presents as chronic endocarditis. Currently, C. burnetii virulence determinants are poorly understood. Characterization of C. burnetii proteins delivered to the host cytosol by the Dot/Icm type IV secretion system will provide candidate therapeutic targets to combat Q fever and will provide needed insight into the interactions between C. burnetii and its host. The goals of the proposed research are to 1) characterize the interaction of C. burnetii plasmid-encoded Dot/Icm substrates with host proteins and 2) determine the role of the plasmid in pathogen virulence.)
Funding Period: 2010-07-01 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc The Coxiella burnetii cryptic plasmid is enriched in genes encoding type IV secretion system substrates
    Daniel E Voth
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 W Markham Street, Little Rock, AR 72205, USA
    J Bacteriol 193:1493-503. 2011
  2. pmc Coxiella burnetii exploits host cAMP-dependent protein kinase signalling to promote macrophage survival
    Laura J Macdonald
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
    Cell Microbiol 16:146-59. 2014
  3. pmc Refining the plasmid-encoded type IV secretion system substrate repertoire of Coxiella burnetii
    Pauline Maturana
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
    J Bacteriol 195:3269-76. 2013
  4. pmc Virulent Coxiella burnetii pathotypes productively infect primary human alveolar macrophages
    Joseph G Graham
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
    Cell Microbiol 15:1012-25. 2013
  5. ncbi Coxiella subversion of intracellular host signaling
    S Kauser Hussain
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 W Markham Street, Little Rock, AR 72205, USA
    Adv Exp Med Biol 984:131-40. 2012
  6. pmc Coxiella burnetii alters cyclic AMP-dependent protein kinase signaling during growth in macrophages
    Laura J Macdonald
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    Infect Immun 80:1980-6. 2012
  7. pmc Bacterial Type IV secretion systems: versatile virulence machines
    Daniel E Voth
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 W Markham, Little Rock, AR 72205, USA
    Future Microbiol 7:241-57. 2012
  8. pmc Identification of Anaplasma marginale type IV secretion system effector proteins
    Svetlana Lockwood
    School of Electrical Engineering and Computer Science, Washington State University, Pullman, Washington, United States of America
    PLoS ONE 6:e27724. 2011
  9. pmc Dot/Icm type IVB secretion system requirements for Coxiella burnetii growth in human macrophages
    Paul A Beare
    Coxiella Pathogenesis Section, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
    MBio 2:e00175-11. 2011
  10. pmc Host Kinase Activity is Required for Coxiella burnetii Parasitophorous Vacuole Formation
    S Kauser Hussain
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences Little Rock, AR, USA
    Front Microbiol 1:137. 2010

Detail Information

Publications12

  1. pmc The Coxiella burnetii cryptic plasmid is enriched in genes encoding type IV secretion system substrates
    Daniel E Voth
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 W Markham Street, Little Rock, AR 72205, USA
    J Bacteriol 193:1493-503. 2011
    ..burnetii plasmid-encoded T4SS substrates play important roles in subversion of host cell functions, providing a plausible explanation for the absolute maintenance of plasmid genes by this pathogen...
  2. pmc Coxiella burnetii exploits host cAMP-dependent protein kinase signalling to promote macrophage survival
    Laura J Macdonald
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
    Cell Microbiol 16:146-59. 2014
    ..burnetii effector(s) regulates PKA-dependent activities. This study is the first to demonstrate subversion of host PKA activity by an intracellular bacterial pathogen to prevent apoptosis and survive within macrophages. ..
  3. pmc Refining the plasmid-encoded type IV secretion system substrate repertoire of Coxiella burnetii
    Pauline Maturana
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
    J Bacteriol 195:3269-76. 2013
    ..These results further support the idea of a critical role for extrachromosomal elements in C. burnetii pathogenesis. ..
  4. pmc Virulent Coxiella burnetii pathotypes productively infect primary human alveolar macrophages
    Joseph G Graham
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
    Cell Microbiol 15:1012-25. 2013
    ..burnetii. Collectively, the current results demonstrate the hAM model is a human disease-relevant platform for defining novel innate immune responses to C. burnetii...
  5. ncbi Coxiella subversion of intracellular host signaling
    S Kauser Hussain
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 W Markham Street, Little Rock, AR 72205, USA
    Adv Exp Med Biol 984:131-40. 2012
    ..Identification of bacterial factors that regulate signaling events will further our ability to model this intriguing infectious process...
  6. pmc Coxiella burnetii alters cyclic AMP-dependent protein kinase signaling during growth in macrophages
    Laura J Macdonald
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    Infect Immun 80:1980-6. 2012
    ..Collectively, the current results suggest a versatile role for PKA in C. burnetii infection and indicate virulent organisms usurp host kinase cascades for efficient intracellular growth...
  7. pmc Bacterial Type IV secretion systems: versatile virulence machines
    Daniel E Voth
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 W Markham, Little Rock, AR 72205, USA
    Future Microbiol 7:241-57. 2012
    ..In this review, we discuss the current state of T4SS research, with an emphasis on intracellular bacterial pathogens of humans and the diverse array of translocated effectors used to manipulate host cells...
  8. pmc Identification of Anaplasma marginale type IV secretion system effector proteins
    Svetlana Lockwood
    School of Electrical Engineering and Computer Science, Washington State University, Pullman, Washington, United States of America
    PLoS ONE 6:e27724. 2011
    ..marginale by translocating effector proteins across its membrane into eukaryotic target cells. However, T4SS effector proteins have not been identified and tested in the laboratory until now...
  9. pmc Dot/Icm type IVB secretion system requirements for Coxiella burnetii growth in human macrophages
    Paul A Beare
    Coxiella Pathogenesis Section, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
    MBio 2:e00175-11. 2011
    ....
  10. pmc Host Kinase Activity is Required for Coxiella burnetii Parasitophorous Vacuole Formation
    S Kauser Hussain
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences Little Rock, AR, USA
    Front Microbiol 1:137. 2010
    ..burnetii subverts numerous phosphorylation cascades. These results underscore the importance of intracellular host signaling for C. burnetii PV biogenesis...
  11. pmc Coxiella burnetii type IV secretion-dependent recruitment of macrophage autophagosomes
    Caylin G Winchell
    Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    Infect Immun 82:2229-38. 2014
    ..Together, these results demonstrate that C. burnetii actively directs PV-autophagosome interactions by using the Dot/Icm T4SS. ..

Research Grants30

  1. CELLULAR AND MOLECULAR BIOLOGY OF LIPOPROTEIN METABOLISM
    Michael C Phillips; Fiscal Year: 2013
    ..The reasons for this protective effect are not understood fully and this project seeks to uncover the molecular mechanisms underlying the beneficial properties of HDL. ..
  2. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
    ..abstract_text> ..
  3. Optimization of HIV vaccines for the induction of cross-reactive antibodies
    Shan Lu; Fiscal Year: 2013
    ..RELEVANCE: To optimize the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime - protein boost technology platform. ..
  4. The UPMC Sexually Transmitted Infections Cooperative Research Center
    Toni Darville; Fiscal Year: 2013
    ..abstract_text> ..
  5. GENETIC ANALYSIS OF LEGIONELLA PHAGOSOME TRAFFICKING
    Craig R Roy; Fiscal Year: 2013
    ....
  6. Small Regulatory RNAs of Coxiella burnetii - The Agent of Q Fever
    JAMES MICHAEL BATTISTI; Fiscal Year: 2013
    ..Moreover, the results will clarify the rol of 6S sRNA in g-proteobacteria, where orthologous s factors play distinctive roles in different bacterial species. ..
  7. 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. ..
  8. 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. ..
  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. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  11. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  12. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  13. The role of acyl-CoA binding proteins in selective autophagy
    Taras Y Nazarko; Fiscal Year: 2013
    ..We expect studies on ACBPs in yeast and mammalian cells will extend our understanding of organelle homeostasis and provide new targets for the prevention and treatment of obesity in humans. ..
  14. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..
  15. Host cell manipulation by Toxoplasma
    Isabelle Coppens; Fiscal Year: 2013
    ..We will explore the connection between Golgi remodeling and lipid salvage by the parasite. Our results may raise the provocative notion of novel treatments against Toxoplasma based on interference with host organelle functions. ..
  16. Cytosolic sensing of intracellular Brucella infection
    Renee M Tsolis; Fiscal Year: 2013
    ..abstract_text> ..
  17. Novel rhoptry effector proteins in Toxoplasma host-pathogen interaction
    PETER JOHN BRADLEY; Fiscal Year: 2013
    ..Together, these complementary approaches promise to reveal novel mechanistic insights into how Toxoplasma uses this unique set of effector proteins to modulate its mammalian host cell. ..
  18. Middle Atlantic Regional Center for Excellence for Biodefense and Emerging Infect
    MYRON MAX LEVINE; Fiscal Year: 2013
    ..abstract_text> ..