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.
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.
|Spaulding, Caitlin N; Schreiber 4th, Henry Louis; Zheng, Weili et al. (2018) Functional role of the type 1 pilus rod structure in mediating host-pathogen interactions. Elife 7:|
|Omattage, Natalie S; Deng, Zengqin; Pinkner, Jerome S et al. (2018) Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli. Nat Microbiol 3:1362-1368|
|Schwan, William R; Beck, Michael T; Hung, Chia S et al. (2018) Differential Regulation of Escherichia coli fim Genes following Binding to Mannose Receptors. J Pathog 2018:2897581|
|Sheikh, Alaullah; Rashu, Rasheduzzaman; Begum, Yasmin Ara et al. (2017) Highly conserved type 1 pili promote enterotoxigenic E. coli pathogen-host interactions. PLoS Negl Trop Dis 11:e0005586|
|Kalas, Vasilios; Pinkner, Jerome S; Hannan, Thomas J et al. (2017) Evolutionary fine-tuning of conformational ensembles in FimH during host-pathogen interactions. Sci Adv 3:e1601944|
|Spaulding, Caitlin N; Klein, Roger D; Ruer, Ségolène et al. (2017) Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature 546:528-532|
|Paharik, Alexandra E; Schreiber 4th, Henry L; Spaulding, Caitlin N et al. (2017) Narrowing the spectrum: the new frontier of precision antimicrobials. Genome Med 9:110|
|Hibbing, Michael E; Conover, Matt S; Hultgren, Scott J (2016) The unexplored relationship between urinary tract infections and the autonomic nervous system. Auton Neurosci 200:29-34|
|Spaulding, Caitlin N; Hultgren, Scott J (2016) Adhesive Pili in UTI Pathogenesis and Drug Development. Pathogens 5:|
|Hospenthal, Manuela K; Redzej, Adam; Dodson, Karen et al. (2016) Structure of a Chaperone-Usher Pilus Reveals the Molecular Basis of Rod Uncoiling. Cell 164:269-278|
Showing the most recent 10 out of 76 publications