Over ten million women suffer from urinary tract infection (UTI) annually. Most UTIs are caused by uropathogenic Escherichia coli (UPEC). Although antibiotics are typically effective, millions of women suffer from chronic recurrences and are often put on long-term suppressive and/or intravenous antibiotic therapy. Clearly, better therapeutic alternatives are critical for improving the lives of those suffering from UTI. Toward this end, studies of how UPEC cause recurrent UTI have revealed that pili assembled by the chaperone/usher pathway (CUP) play a critical role;abolishing the function of CUP pili renders UPEC noninfectious. CUP pili are comprised of multiple subunits with partial immunoglobulin folds. Previous work has shown that these partial folds are completed by adjacent subunits within the assembled pilus. Prior to assembly, a dedicated chaperone protein temporarily completes these folds. These exquisitely specific chaperone-subunit and subunit-subunit interactions are prime targets for treatment of UTI and other pili-related diseases. During infection, CUP pili mediate colonization, tissue invasion, and biofilm formation. Type 1 pili, for example, mediate the binding and invasion of UPEC into bladder epithelial cells, where they replicate rapidly in the cytoplasm. Simultaneously, the expression of type 1 pili facilitates the aggregation of the invaded organisms into a biofilm-like intracellular bacterial community (IBC) that protects the bacteria from host defenses and antibiotics. CUP pili are also important in biofilm formation on catheters and other surfaces in nosocomial settings. Individual E. coli can encode over ten CUP operons that likely are important in UTI or other infections, yet few have been studied. Therefore, an understanding of the contribution of CUP pili to biofilm formation and the regulation of their expression is also central to combating these infections. This proposal outlines a concerted research program to elucidate the complexity of fiber systems biology and its relation to disease. In vitro and in vivo models, genetics, imaging, and biochemical and biophysical techniques will be used to understand: fiber polymerization (aim 1);the role of CUP pili in biofilm formation (aim 2);and the regulation of expression of the multiple CUP operons in the E. coli genome (aim 3). These studies will increase the understanding of the fiber arsenal used by UPEC and other bacteria to cause problematic infections (such as UTI or catheter-associated infections). Knowledge of these pili is leading to the development of small molecules that block pilus assembly and/or function and thereby infection.

Public Health Relevance

Extracellular fibers are crucial virulence factors for uropathogenic E. coli and other bacteria. Chaperone/usher pili, in particular, mediate colonization, invasion, and biofilm formation, thus contributing to bacterial survival, replication, and resistance to host defenses and antibiotics. Detailed knowledge of extracellular fiber assembly, regulation, and function is paramount for enabling the design of new therapeutic approaches to disarm and combat these infections, many of which are chronic and plagued by antibiotic resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048689-13
Application #
8417692
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Korpela, Jukka K
Project Start
2001-02-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
13
Fiscal Year
2013
Total Cost
$357,200
Indirect Cost
$122,200
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
O'Brien, Valerie P; Hannan, Thomas J; Nielsen, Hailyn V et al. (2016) Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections. Microbiol Spectr 4:
Spaulding, Caitlin N; Hultgren, Scott J (2016) Adhesive Pili in UTI Pathogenesis and Drug Development. Pathogens 5:
Conover, Matt S; Ruer, Ségolène; Taganna, Joemar et al. (2016) Inflammation-Induced Adhesin-Receptor Interaction Provides a Fitness Advantage to Uropathogenic E. coli during Chronic Infection. Cell Host Microbe 20:482-492
Hospenthal, Manuela K; Redzej, Adam; Dodson, Karen et al. (2016) Structure of a Chaperone-Usher Pilus Reveals the Molecular Basis of Rod Uncoiling. Cell 164:269-78
O'Brien, Valerie P; Hannan, Thomas J; Schaeffer, Anthony J et al. (2015) Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection. Curr Opin Infect Dis 28:97-105
Van Gerven, Nani; Klein, Roger D; Hultgren, Scott J et al. (2015) Bacterial amyloid formation: structural insights into curli biogensis. Trends Microbiol 23:693-706
Greene, Sarah E; Hibbing, Michael E; Janetka, James et al. (2015) Human Urine Decreases Function and Expression of Type 1 Pili in Uropathogenic Escherichia coli. MBio 6:e00820
Lin, Ann E; Beasley, Federico C; Olson, Joshua et al. (2015) Role of Hypoxia Inducible Factor-1α (HIF-1α) in Innate Defense against Uropathogenic Escherichia coli Infection. PLoS Pathog 11:e1004818
Greene, Sarah E; Pinkner, Jerome S; Chorell, Erik et al. (2014) Pilicide ec240 disrupts virulence circuits in uropathogenic Escherichia coli. MBio 5:e02038
Lim, Ji Youn; Pinkner, Jerome S; Cegelski, Lynette (2014) Community behavior and amyloid-associated phenotypes among a panel of uropathogenic E. coli. Biochem Biophys Res Commun 443:345-50

Showing the most recent 10 out of 68 publications