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 the second most common bacterial infection of humans and the most common kidney and urologic disease in the U.S. The most common uropathogen, Escherichia coli, causes 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 is blocked by structural abnormality or urethral catheters, Proteus mirabilis may 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 and should not be employed at the same time. We have provided significant evidence and developed the theme that E. coli and P. mirabilis possess defined regulatory pathways by which they transition from the adherent to the motile form and display unique phenotypes associated with each lifestyle. Genes expressed during these opposite lifestyles govern the biology of infection of the urinary tract. Terminal genes in adherence gene operons of both pathogens have been demonstrated to specifically repress motility. However, when these phase variable fimbrial operons are in the off phase, flagella are expressed. In P. mirabilis, MrpJ (a PapX homolog) encoded by the MR/P fimbrial operon, inhibits swarming. When MR/P fimbriae are phase off, P. mirabilis differentiates into highly motile swarmer cells and induces a type 6 secretion system to kill competitors. In E. coli, the P fimbrial operon gene product PapX and the non-fimbrial TosA operon gene products TosE and TosF repress flagellar synthesis. These compelling phenotypes will be the subject of investigation. In this proposal, we will advance the central hypothesis that uropathogenic E. coli and P. mirabilis regulate adherence and motility resulting in distinct patterns of gene expression that are advantageous during infection of the urinary tract. We will test this hypothesis by carrying out the following specific aims: 1) Determine the mechanism of interbacterial killing by the swarming-induced type VI secretion system in Proteus mirabilis. 2) Determine the mechanism of repression of motility by regulatory genes in the pap and tos adherence operons in uropathogenic E. coli. This contribution will be significant because two of the principal virulence properties of E. coli and P. mirabilis are adherence and motility. Understanding the mechanisms by which these species regulate these critical traits and defining the phenotypes associated with each phase will advance our knowledge of these pathogens. By implementing our specific aims, we will elucidate regulatory pathways that govern two critical functions, motility and adherence, which will provide the opportunity to identify novel targets for development of new antimicrobial agents.

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 in place to help with urination, Proteus mirabilis often infects the bladder and causes stones to form. This study will determine how these bacteria decide to adhere to host cells or to swim up the ureters to the kidney. The proposed research is relevant to public health because understanding how these bacteria colonize the urinary tract 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 #
5R01AI059722-14
Application #
9617187
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Ernst, Nancy L
Project Start
2004-04-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
14
Fiscal Year
2019
Total Cost
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; 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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