Klebsiella pneumoniae is an opportunistic pathogen frequently implicated in respiratory and urinary tract infections of hospitalized patients. In addition, it is a leading cause of pneumonia in chronic alcoholics and has also been associated with community acquired pneumonia. Infections are particularly difficult to treat since most clinical isolates exhibit resistance to several antibiotics leading to treatment failure. In the human respiratory tract it has been suggested that K. pneumoniae can exist as a biofilm growing on lung tissue. These bacteria produce copious amounts of an acidic polysaccharide capsule that has been shown to possess antiphagocytic properties and the capsule is believed to be an important virulence factor. However, relatively little is known about other virulence determinants produced by these bacteria which allow them to colonize and grow on perturbed epithelial tissues, invade into the bloodstream and successfully overcome host defense mechanisms. In this proposal we describe studies to continue our investigations into the molecular pathogenetic mechanisms of K. pneumoniae. We will use flow-through biofilm chambers coated with human-derived extracellular matrices to determine the role of fimbrial types and other gene products in forming a biofilm on these biotic surfaces. In complementary studies a murine model of acute infection will be utilized to examine the role of putative virulence factors in vivo. In many other pathogenic bacteria the genetic regulation of virulence factor expression involves a complex regulatory network or regulon. We describe in this proposal two series of studies to examine regulators that play an important role in influencing the ability of the bacteria to cause infections in vivo and grow on human matrices in vitro. The targets of these regulatory genes will be determined. In addition, like many other enteric bacteria, K. pneumoniae posses the ability to produce several different types of fimbriae or pili. The coordinate production of distinct fimbrial types has not been investigated in detail in any bacterial species. The isolation of mutations that cause alteration in at least two types of fimbrial expression will allow us to begin to characterize the fimbrial regulon. In summary the aims of this proposal are to elucidate the role of fimbriae in K. pneumoniae pathogenesis, to investigate the regulatory pathways affecting virulence, and to define virulence gene expression during biofilm growth.

Public Health Relevance

This project investigates mechanisms used by the bacterium Klebsiella pneumoniae to cause infections of the airways. These bacteria frequently cause airway infections in hospitalized patients,

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Taylor, Christopher E,
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University of Iowa
Schools of Medicine
Iowa City
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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
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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
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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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