The urinary tract is a complicated epithelial-lined tube with an opening to the body surface, making it susceptible to infection by exogenous organisms. Indeed, urinary tract infection is one of the most common bacterial infections of humans and the most common kidney and urologic disease in the US. The most common uropathogen, Escherichia coli, can cause acute cystitis or pyelonephritis in the uncomplicated urinary tract. On the other hand, in patients with complicated urinary tracts, ones in which normal urine flow are blocked by structural abnormality or urethral catheters, species such as Proteus mirabilis predominate. Both E. coli and P. mirabilis are members of the Enterobacteriaceae, are motile, and produce a battery of fimbriae by which they mediate adherence to the uroepithelium. The abilities to swim using flagella and to adhere by certain fimbriae have been demonstrated to be virulence traits for both organisms. However the actions of the two organelles have opposite functions. We reason that there is a time to swim and a time to adhere. We also provide preliminary data that E. coli and P. mirabilis possess defined regulatory pathways by which they transform from the motile to the adherent form and vice versa. As well, other regulatory mechanisms have been uncovered. In this proposal, we will test the central hypothesis that uropathogenic E. coli and P. mirabilis strictly regulate the balance between motility and adherence. We will test this hypothesis by carrying out the following specific aims: 1) Elucidate the prevalence, function, structure, and contribution to virulence of fimbrial operon-encoded repressors of motility: PapX and MrpJ;and 2) Define the regulatory pathways for proteins that mediate reciprocal regulation between fimbriation and motility. Clearly the ability to colonize mucosal surfaces in the respiratory, intestinal, and genital tracts also require the orchestrated synthesis of fimbriae for adherence and flagella for motility.

Public Health Relevance

The urinary tract is susceptible to infection by bacteria. Indeed, urinary tract infection is one of the most common bacterial infections of humans. The most common bacterium that infects the urinary tract of healthy individuals is Escherichia coli. On the other hand, in patients who have urinary catheters to help with urination, a bacterium called Proteus mirabilis often infects the bladder and causes stones to form there. Both of these bacteria can either stick to the surface of the bladder or swim up to the kidneys. But they should not do both. This study will determine how these bacteria decide to stick or decide to swim. Understanding how these bacteria cause urinary tract infection will help us to develop antimicrobial agents and vaccines to combat these infections that each year costs the United States nearly 3 billion dollars to treat.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059722-08
Application #
8463958
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Korpela, Jukka K
Project Start
2004-04-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
8
Fiscal Year
2013
Total Cost
$349,354
Indirect Cost
$116,704
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Armbruster, Chelsie E; Mobley, Harry L T; Pearson, Melanie M (2018) Pathogenesis of Proteus mirabilis Infection. EcoSal Plus 8:
Luterbach, Courtney L; Forsyth, Valerie S; Engstrom, Michael D et al. (2018) TosR-Mediated Regulation of Adhesins and Biofilm Formation in Uropathogenic Escherichia coli. mSphere 3:
Sintsova, Anna; Smith, Sara; Subashchandrabose, Sargurunathan et al. (2018) Role of Ethanolamine Utilization Genes in Host Colonization during Urinary Tract Infection. Infect Immun 86:
Debnath, Irina; Stringer, Anne M; Smith, Sara N et al. (2018) MrpJ Directly Regulates Proteus mirabilis Virulence Factors, Including Fimbriae and Type VI Secretion, during Urinary Tract Infection. Infect Immun 86:
Armbruster, Chelsie E; Smith, Sara N; Mody, Lona et al. (2018) Urine cytokine and chemokine levels predict urinary tract infection severity independent of uropathogen, urine bacterial burden, host genetics, and host age. Infect Immun :
Dbeibo, Lana; van Rensburg, Julia J; Smith, Sara N et al. (2018) Evaluation of CpxRA as a Therapeutic Target for Uropathogenic Escherichia coli Infections. Infect Immun 86:
Forsyth, Valerie S; Armbruster, Chelsie E; Smith, Sara N et al. (2018) Rapid Growth of Uropathogenic Escherichia coli during Human Urinary Tract Infection. MBio 9:
Luterbach, Courtney L; Mobley, Harry L T (2018) Cross Talk between MarR-Like Transcription Factors Coordinates the Regulation of Motility in Uropathogenic Escherichia coli. Infect Immun 86:
Armbruster, Chelsie E; Forsyth-DeOrnellas, Valerie; Johnson, Alexandra O et al. (2017) Genome-wide transposon mutagenesis of Proteus mirabilis: Essential genes, fitness factors for catheter-associated urinary tract infection, and the impact of polymicrobial infection on fitness requirements. PLoS Pathog 13:e1006434
Alteri, Christopher J; Himpsl, Stephanie D; Zhu, Kevin et al. (2017) Subtle variation within conserved effector operon gene products contributes to T6SS-mediated killing and immunity. PLoS Pathog 13:e1006729

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