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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050011-04
Application #
7047874
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Taylor, Christopher E,
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$288,068
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Murphy, Caitlin N; Mortensen, Martin S; Krogfelt, Karen A et al. (2013) 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. Infect Immun 81:3009-17
Stahlhut, Steen G; Chattopadhyay, Sujay; Kisiela, Dagmara I et al. (2013) Structural and population characterization of MrkD, the adhesive subunit of type 3 fimbriae. J Bacteriol 195:5602-13
Johnson, Jeremiah G; Murphy, Caitlin N; Sippy, Jean et al. (2011) Type 3 fimbriae and biofilm formation are regulated by the transcriptional regulators MrkHI in Klebsiella pneumoniae. J Bacteriol 193:3453-60
Johnson, Jeremiah G; Clegg, Steven (2010) Role of MrkJ, a phosphodiesterase, in type 3 fimbrial expression and biofilm formation in Klebsiella pneumoniae. J Bacteriol 192:3944-50
Hung, Chia-Suei; Dodson, Karen W; Hultgren, Scott J (2009) A murine model of urinary tract infection. Nat Protoc 4:1230-43
Rosen, David A; Pinkner, Jerome S; Jones, Jennifer M et al. (2008) Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of FimK on type 1 pilus expression. Infect Immun 76:3337-45
Lau, Helen Y; Clegg, Steven; Moore, Thomas A (2007) Identification of Klebsiella pneumoniae genes uniquely expressed in a strain virulent using a murine model of bacterial pneumonia. Microb Pathog 42:148-55
Mehling, Joanna S; Lavender, Heather; Clegg, Steven (2007) A Dam methylation mutant of Klebsiella pneumoniae is partially attenuated. FEMS Microbiol Lett 268:187-93
Boddicker, Jennifer D; Anderson, Rebecca A; Jagnow, Jennifer et al. (2006) Signature-tagged mutagenesis of Klebsiella pneumoniae to identify genes that influence biofilm formation on extracellular matrix material. Infect Immun 74:4590-7
Esteves, Cristina L C; Jones, Bradley D; Clegg, Steven (2005) Biofilm formation by Salmonella enterica serovar Typhimurium and Escherichia coli on epithelial cells following mixed inoculations. Infect Immun 73:5198-203

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