Pathogenesis of Klebsiells airway infections

Summary

Principal Investigator: Steven Clegg
Affiliation: University of Iowa
Country: USA
Abstract: The opportunistic pathogen, Klebsiella pneumoniae, is responsible for a significant number of pulmonary infections in compromised individuals. The ubiquity of antibiotic resistant strains, particularly those producing extended-spectrum beta-lactamases, presents a serious clinical problem among groups such as hospitalized individuals and chronic alcoholics. The pathogenesis of Klebsiella airway infections has not been studied to any great extent and the investigation of the production of virulence determinants has essentially focused upon the role of capsules as antiphagocytic factors. The mouse has been extensively used as a model of airway infections due to K. pneumoniae primarily to investigate host cell responses. Also, epidemiologic observations suggest that specific capsular serotypes (e.g. K2) are most frequently associated with pulmonary infections. However, our preliminary data indicate that not all K2-positive isolates are virulent in the mouse model of infection. Therefore, although the capsule is most likely to be an antiphagocytic factor and prevent efficient killing of the bacteria in vivo, additional factors are necessary to establish airway infections with subsequent invasion of the bloodstream. We propose to identify and confirm the role of previously unknown virulence factors that mediate airway infections due to K. pneumoniae. Three techniques; signature-tagged mutagenesis, subtractive hybridization and in vivo gene expression technology will identify these determinants. The murine model of Klebsiella infection will be used to demonstrate the role of putative virulence factors during infection. The three approaches are complementary and have been used to investigate virulence in many different types of pathogens. Since very little is known about the virulence factors of K. pneumoniae, it is anticipated that these studies will provide information on new and novel virulence factors produced by these bacteria. Fundamental to devising new therapeutic approaches to opportunistic infections will be an understanding of the virulence factors produced by this group of organisms.
Funding Period: 2003-04-01 - 2009-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Klebsiella pneumoniae type 3 fimbria-mediated immunity to infection in the murine model of respiratory disease
    Heather Lavender
    College of Medicine, Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
    Int J Med Microbiol 295:153-9. 2005
  2. pmc Structural and population characterization of MrkD, the adhesive subunit of type 3 fimbriae
    Steen G Stahlhut
    Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark
    J Bacteriol 195:5602-13. 2013
  3. pmc Role of Klebsiella pneumoniae type 1 and type 3 fimbriae in colonizing silicone tubes implanted into the bladders of mice as a model of catheter-associated urinary tract infections
    Caitlin N Murphy
    Department of Microbiology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
    Infect Immun 81:3009-17. 2013
  4. pmc Type 3 fimbriae and biofilm formation are regulated by the transcriptional regulators MrkHI in Klebsiella pneumoniae
    Jeremiah G Johnson
    Department of Microbiology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Bacteriol 193:3453-60. 2011
  5. pmc Role of MrkJ, a phosphodiesterase, in type 3 fimbrial expression and biofilm formation in Klebsiella pneumoniae
    Jeremiah G Johnson
    Department of Microbiology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Bacteriol 192:3944-50. 2010
  6. pmc A murine model of urinary tract infection
    Chia Suei Hung
    Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri, USA
    Nat Protoc 4:1230-43. 2009
  7. pmc Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of FimK on type 1 pilus expression
    David A Rosen
    Department of Molecular Microbiology, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, USA
    Infect Immun 76:3337-45. 2008
  8. pmc Identification of Klebsiella pneumoniae genes uniquely expressed in a strain virulent using a murine model of bacterial pneumonia
    Helen Y Lau
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
    Microb Pathog 42:148-55. 2007
  9. ncbi A Dam methylation mutant of Klebsiella pneumoniae is partially attenuated
    Joanna S Mehling
    Department of Microbiology, The University of Iowa, Iowa City, IA 52242, USA
    FEMS Microbiol Lett 268:187-93. 2007
  10. pmc Signature-tagged mutagenesis of Klebsiella pneumoniae to identify genes that influence biofilm formation on extracellular matrix material
    Jennifer D Boddicker
    Department of Microbiology, College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Infect Immun 74:4590-7. 2006

Detail Information

Publications11

  1. ncbi Klebsiella pneumoniae type 3 fimbria-mediated immunity to infection in the murine model of respiratory disease
    Heather Lavender
    College of Medicine, Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
    Int J Med Microbiol 295:153-9. 2005
    ..However, challenge with a high number of bacteria resulted in no protection against infection...
  2. pmc Structural and population characterization of MrkD, the adhesive subunit of type 3 fimbriae
    Steen G Stahlhut
    Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark
    J Bacteriol 195:5602-13. 2013
    ....
  3. pmc Role of Klebsiella pneumoniae type 1 and type 3 fimbriae in colonizing silicone tubes implanted into the bladders of mice as a model of catheter-associated urinary tract infections
    Caitlin N Murphy
    Department of Microbiology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
    Infect Immun 81:3009-17. 2013
    ..Using these methods, we are able to show that type 1 and type 3 fimbriae are important colonization factors in the murine urinary tract when an implanted silicone tube is present. ..
  4. pmc Type 3 fimbriae and biofilm formation are regulated by the transcriptional regulators MrkHI in Klebsiella pneumoniae
    Jeremiah G Johnson
    Department of Microbiology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Bacteriol 193:3453-60. 2011
    ..This gene was found to be cotranscribed with a gene predicted to encode a PilZ domain-containing protein, designated MrkH. This protein was found to bind cyclic-di-GMP (c-di-GMP) and regulate type 3 fimbrial expression...
  5. pmc Role of MrkJ, a phosphodiesterase, in type 3 fimbrial expression and biofilm formation in Klebsiella pneumoniae
    Jeremiah G Johnson
    Department of Microbiology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Bacteriol 192:3944-50. 2010
    ..These results reveal a previously unknown role for cyclic-di-GMP in type 3 fimbrial production...
  6. pmc A murine model of urinary tract infection
    Chia Suei Hung
    Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri, USA
    Nat Protoc 4:1230-43. 2009
    ..Nevertheless, one should expect 4 h of hands-on time, including inoculum preparation on the day of infection, transurethral inoculation, tissue harvest and post-harvest processing for a small group of mice (e.g., 5 mice)...
  7. pmc Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of FimK on type 1 pilus expression
    David A Rosen
    Department of Molecular Microbiology, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, USA
    Infect Immun 76:3337-45. 2008
    ..Thus, K. pneumoniae appears programmed for minimal expression of type 1 pili, which may explain, in part, why K. pneumoniae is a less prevalent etiologic agent of UTI than UPEC...
  8. pmc Identification of Klebsiella pneumoniae genes uniquely expressed in a strain virulent using a murine model of bacterial pneumonia
    Helen Y Lau
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
    Microb Pathog 42:148-55. 2007
    ....
  9. ncbi A Dam methylation mutant of Klebsiella pneumoniae is partially attenuated
    Joanna S Mehling
    Department of Microbiology, The University of Iowa, Iowa City, IA 52242, USA
    FEMS Microbiol Lett 268:187-93. 2007
    ..In K. pneumoniae, a mutation-eliminating Dam function is shown here to result in only partial attenuation following intranasal and intraperitoneal infection of Balb/C mice...
  10. pmc Signature-tagged mutagenesis of Klebsiella pneumoniae to identify genes that influence biofilm formation on extracellular matrix material
    Jennifer D Boddicker
    Department of Microbiology, College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Infect Immun 74:4590-7. 2006
    ..We identified mutations in the cps capsule gene cluster, previously unidentified transcriptional regulators, fimbrial, and sugar phosphotransferase homologues, as well as genetic loci of unknown function, that affect biofilm formation...
  11. pmc Biofilm formation by Salmonella enterica serovar Typhimurium and Escherichia coli on epithelial cells following mixed inoculations
    Cristina L C Esteves
    Department of Microbiology, University of Iowa College of Medicine, 51 Newton Road, 3334 BSB, Iowa City, IA 52242, USA
    Infect Immun 73:5198-203. 2005
    ..enterica serovar Typhimurium. The results of this study indicate that S. enterica serovar Typhimurium can outgrow E. coli in heterologous infections and displace E. coli when it forms a biofilm on HEp-2 cells...