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 #
5R01AI059722-13
Application #
9399605
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Ernst, Nancy L
Project Start
2004-04-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
13
Fiscal Year
2018
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; 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:

Showing the most recent 10 out of 61 publications