Faculty

Bacterial pathogenesis; virulence of uropathogens and Helicobacter pylori

    My laboratory is interested in the molecular mechanisms of bacterial pathogenesis. We are studying virulence mechanisms of uropathogenic Escherichia coli and Proteus mirabilis that cause urinary tract infection and Helicobacter pylori that causes gastritis and peptic ulcer disease.

    For E. coli, we are investigating the contribution to virulence of the phase variable expression of type 1 fimbriae. In particularly, we are interested in phase variation in vivo using an experimental murine model of urinary tract infection. Pyelonephritogenic and cystitis strains also appear to secrete specific proteins not exported by non-virulent fecal strains. For example, uropathogenic strains express the secreted autotransporter toxin, Sat, which specifically vacuolates bladder and kidney epithelial cells. Two other autotransporter proteins, Pic and Tsh, are also secreted by these strains. We are also currently investigating gene expression in uropathogenic E. coli during experimental urinary tract infection and identifying vaccine candidate antigens.

    For Proteus mirabilis, we are investigating the reciprocal control of adherence by MR/P fimbriae and motility. We reason that bacteria should not be both adherent and motile simultaneously. Potential regulators have been identified and are under investigation. We are also using signature-tagged mutagenesis in conjunction with the murine model of urinary tract infection to identify virulence determinants that otherwise have no obvious phenotype. More than 25 mutants have been identified that are attenuated at least 100-fold in vivo. We are also investigating in vivo gene expression by this bacterium during experimental urinary tract infection.

    In addition, we are investigating the role of urease in the pathogenesis of peptic ulcer disease caused by Helicobacter pylori. Other bacterial proteins that either bind or transport nickel ions, which are components of the enzyme active site and required for activity, are being examined with respect to their role in the synthesis of a catalytically active holoenzyme.

Selected Publications:

    Snyder, J.A., A.L. Lloyd, C.V. Lockatell, D.E. Johnson, and H.L.T. Mobley.  2006.  Role of phase variation of type 1 fimbriae in a uropathogenic Escherichia coli cysititis isolate during urinary tract infection. Infect. Immun. 74:1387-1393.

    Lane, M. Chelsea, Amanda L. Lloyd, Tiffany A. Markyvech, Erin C. Hagan, and Harry L.T. Mobley.  2006.  Uropathogenic Escherichia coli Generally Lack Functional Trg and Tap Chemoreceptors Found in the Majority of E. coli Strictly Residing in the Gut. J. Bacteriol. 188:5618-5625.

    Maroncle, Nathalie M., Kelsey E. Sivick, Rebecca Brady, Faye-Ellen Stokes, and Harry L.T. Mobley.  2006.  Protease Activity, Secretion, Cell Entry, Cytotoxicity, and Cellular Targets of  Secreted Autotransporter Toxin of uropathogenic Escherichia coli.  Infect. Immun. 74:6124-6134.

    Davis, Gregg S., Erika L. Flannery, and Harry L.T. Mobley.  2006.  Helicobacter pylori HP1512 is a Nickel-Responsive NikR-Regulated Outer Membrane Protein.  Infect. Immun. 74:6811-6820.

    Lloyd, Amanda L., David A. Rasko, and Harry L.T. Mobley.  2007.  Defining genomic islands and uropathogen-specific genes in uropathogenic E . coli.  J. Bacteriol. 189:3532-3546.

    Alteri, Christopher J. and Harry L.T. Mobley.  2007.  Quantitative profile of the uropathogenic Escherichia coli outer membrane proteome during growth in human urine Infect. Immun. 75:2679-2688.

    Lane, M.C. and H.L.T. Mobley.  2007.  Role of P-fimbrial-mediated adherence in pyelonephritis and persistence of uropathogenic Escherichia coli (UPEC) in the mammalian kidney.  Kidney Int. 72:19-25.

    Lane, M. Chelsea*, Amy N. Simms*, and Harry L.T. Mobley.  2007.  Complex interplay between type 1 fimbrial expression and flagellum-mediated motility of uropathogenic Escherichia coli.  J. Bacteriol. 189:5523-5533.   [*contributed equally].

    Hagan, Erin C. and Harry L.T. Mobley.  2007.  Uropathogenic Escherichia coli outer membrane antigens expressed during urinary tract infection.  Infect. Immun. 75:3941-3949.

    Pearson M.M. and H.L.T. Mobley.  2007.  The type III secretion system of Proteus mirabilis HI4320 does not contribute to virulence in the mouse model of ascending urinary tract infection. J. Med. Microbiol. (in press).

    Lane, M. Chelsea, Christopher J. Alteri, Sara Smith, and Harry L.T. Mobley.  2007.  Expression of flagella is coincident with uropathogenic Escherichia coli ascension to the upper urinary tract.  Proc. Natl. Acad. Sci. 104:16669-16674.

    Jacobsen, S.M., D.J. Stickler, H.L.T. Mobley, and M.E. Shirtliff.  2008.  Complicated  Urinary Tract Infections Associated with Catheters due to Escherichia coli and Proteus mirabilis.  Clin. Microbiol. Rev. 21:26-59.

    Jacobsen, Sandra M., Mary C. Lane, Jean M. Harro, Mark E. Shirtliff, Harry L.T. Mobley.  2008.  The High-Affinity Phosphate Transporter Pst is a virulence factor for Proteus mirabilis during Complicated Urinary Tract Infection. FEMS Immunol. Med. Microbiol. 52:180-193.

    Alamuri, Praveen and Harry L.T. Mobley.  2008.  A Novel Autotransporter of Uropathogenic Proteus mirabilis is both a Cytotoxin and an Agglutinin. Molec. Microbiol. (in press)

    Simms, Amy N. and Harry L.T. Mobley.  2008.  Multiple genes repress motility in uropathogenic Escherichia coli constitutively expressing type 1 fimbriae.  J. Bacteriol.  (in press).

    Pearson, Melanie M., Mohammed Sebaihia, Carol Churcher, Michael A. Quail, Zahra Abdellah, Claire Arrosmith, Becky Atkin, Tracey Chillingworth, Heidi Hauser, Kay Jagels, Sharon Moule, Karen Mungall, Halina Norbertczak, Ester Rabbinowitsch, Danielle Walker, Sally Whithead, Nicholas R. Thomson, Philip N. Rather, Julian Parkhill, and Harry L. T. Mobley. The Complete genome sequence of Proteus mirabilis, a master of both adherence and motility. J. Bacteriol. (in press).

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