Our long-term goal is to advance the understanding, at the molecular level, of the pathogenicity and epidemiology of uropathogenic Escherichia coli (UPEC) strains to better target treatment and prophylaxis of urinary tract infections, reduce resistance, and provide information on possible targets for vaccines and antibiotics. The proposed studies are focused on understanding the basis of urovirulence of E. coli by the comparative genome-wide analysis of strains that will be isolated from a large number of patients with first-time and recurrent cystitis and healthy women. The central hypothesis is that the relatively few clonal groups involved in UPEC human pathogenesis can be defined and characterized as to their key genetic loci and the impact of genetic variations on UPEC virulence. Our preliminary data support that we can investigate sizeable samples of fresh isolates, establish strong clonal associations with recurrent cystitis and determine genome- wide the pathogenicity-adaptive genetic changes. We will determine how mutational changes (single nucleotide polymorphisms, small insertions/deletions, etc) and horizontal gene transfer contribute to the emergence of UPEC.
Our aim i s to potentially examine every gene shared by at least a portion of UPEC strains for being under positive selection for pathogenicity-adaptive mutations or horizontal transfer. For this, we will employ a population genomics-based analysis to trace the mutations and gene transfer, followed by assessment of the functional significance of the representative positively selected loci in UPEC.

Public Health Relevance

In practical terms, accomplishment of the proposed studies will advance at the molecular level our understanding of the pathogenicity and epidemiology of UPEC strains and will provide information on possible targets for vaccines, antibiotics, or other therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI106007-05
Application #
9379451
Study Section
Urologic and Genitourinary Physiology and Pathology (UGPP)
Program Officer
Ernst, Nancy L
Project Start
2013-11-19
Project End
2019-10-31
Budget Start
2017-11-01
Budget End
2019-10-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Tchesnokova, Veronika; Avagyan, Hovhannes; Rechkina, Elena et al. (2017) Bacterial clonal diagnostics as a tool for evidence-based empiric antibiotic selection. PLoS One 12:e0174132
Kisiela, Dagmara I; Radey, Matthew; Paul, Sandip et al. (2017) Inactivation of Transcriptional Regulators during Within-Household Evolution of Escherichia coli. J Bacteriol 199:
Roer, Louise; Tchesnokova, Veronika; Alles√łe, Rosa et al. (2017) Development of a Web Tool for Escherichia coli Subtyping Based on fimH Alleles. J Clin Microbiol 55:2538-2543
Johnson, James R; Thuras, Paul; Johnston, Brian D et al. (2016) The Pandemic H30 Subclone of Escherichia coli Sequence Type 131 Is Associated With Persistent Infections and Adverse Outcomes Independent From Its Multidrug Resistance and Associations With Compromised Hosts. Clin Infect Dis 62:1529-1536
Johnson, Timothy J; Danzeisen, Jessica L; Youmans, Bonnie et al. (2016) Separate F-Type Plasmids Have Shaped the Evolution of the H30 Subclone of Escherichia coli Sequence Type 131. mSphere 1:
Paul, Sandip; Sokurenko, Evgeni V; Chattopadhyay, Sujay (2016) Corrected Genome Annotations Reveal Gene Loss and Antibiotic Resistance as Drivers in the Fitness Evolution of Salmonella enterica Serovar Typhimurium. J Bacteriol 198:3152-3161
Stoesser, Nicole; Sheppard, Anna E; Pankhurst, Louise et al. (2016) Evolutionary History of the Global Emergence of the Escherichia coli Epidemic Clone ST131. MBio 7:e02162
Leatham-Jensen, Mary P; Mokszycki, Matthew E; Rowley, David C et al. (2016) Uropathogenic Escherichia coli Metabolite-Dependent Quiescence and Persistence May Explain Antibiotic Tolerance during Urinary Tract Infection. mSphere 1:
Johnson, Timothy J; Aziz, Maliha; Liu, Cindy M et al. (2016) Complete Genome Sequence of a CTX-M-15-Producing Escherichia coli Strain from the H30Rx Subclone of Sequence Type 131 from a Patient with Recurrent Urinary Tract Infections, Closely Related to a Lethal Urosepsis Isolate from the Patient's Sister. Genome Announc 4:
Tchesnokova, Veronika; Avagyan, Hovhannes; Billig, Mariya et al. (2016) A Novel 7-Single Nucleotide Polymorphism-Based Clonotyping Test Allows Rapid Prediction of Antimicrobial Susceptibility of Extraintestinal Escherichia coli Directly From Urine Specimens. Open Forum Infect Dis 3:ofw002

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