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 #
2R01AI059722-05A1
Application #
7781030
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
2010-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$374,260
Indirect Cost
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; 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
Anderson, Mark T; Mitchell, Lindsay A; Zhao, Lili et al. (2017) Capsule Production and Glucose Metabolism Dictate Fitness during Serratia marcescens Bacteremia. MBio 8:
Anderson, Mark T; Mitchell, Lindsay A; Mobley, Harry L T (2017) Cysteine Biosynthesis Controls Serratia marcescens Phospholipase Activity. J Bacteriol 199:
Armbruster, Chelsie E; Smith, Sara N; Johnson, Alexandra O et al. (2017) The Pathogenic Potential of Proteus mirabilis Is Enhanced by Other Uropathogens during Polymicrobial Urinary Tract Infection. Infect Immun 85:
Alteri, Christopher J; Mobley, Harry L T (2016) The Versatile Type VI Secretion System. Microbiol Spectr 4:
Engstrom, Michael D; Mobley, Harry L T (2016) Regulation of Expression of Uropathogenic Escherichia coli Nonfimbrial Adhesin TosA by PapB Homolog TosR in Conjunction with H-NS and Lrp. Infect Immun 84:811-21
Buckles, Eric L; Luterbach, Courtney L; Wang, Xiaolin et al. (2015) Signature-tagged mutagenesis and co-infection studies demonstrate the importance of P fimbriae in a murine model of urinary tract infection. Pathog Dis 73:
Subashchandrabose, Sargurunathan; Mobley, Harry L T (2015) Back to the metal age: battle for metals at the host-pathogen interface during urinary tract infection. Metallomics 7:935-42
Brumbaugh, Ariel R; Smith, Sara N; Subashchandrabose, Sargurunathan et al. (2015) Blocking yersiniabactin import attenuates extraintestinal pathogenic Escherichia coli in cystitis and pyelonephritis and represents a novel target to prevent urinary tract infection. Infect Immun 83:1443-50
Alteri, Christopher J; Mobley, Harry L T (2015) Metabolism and Fitness of Urinary Tract Pathogens. Microbiol Spectr 3:

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