The urinary tract is among the most common sites of bacterial infection and E. coli is by far the most common species infecting this site. Most data regarding expression of uropathogenic E. coli (UPEC) virulence genes have come from in vitro studies or the murine model of urinary tract infection (UTI). To remedy this, we have measured global gene expression from E. coli in urine collected and stabilized immediately from women presenting with uncomplicated UTI. These new RNAseq data allow us to focus on the most highly expressed virulence mechanisms active during human infection. Our long term research goal is to understand how UPEC colonize the human urinary tract, avoid the immune response, and damage the host. The objective during this funding period is to determine the contribution to pathogenesis of the virulence genes found to be specifically upregulated in the human host. Our central hypothesis, that the virulence of a UPEC strain is the sum of its capacity for adherence, iron acquisition, toxin production and specific metabolite transport, is supported by our measurements of global gene expression patterns of UPEC during UTI in five women attending the University Health Service Clinic at the University of Michigan for the symptoms of cystitis. The rationale for the proposed work is that once we identify the most highly expressed virulence genes during UTI in humans, we can focus efforts on intervention and prevention directed toward these specific targets. We will test our central hypothesis and complete our objectives by carrying out two specific aims: 1) Determine the representative transcriptome for uropathogenic E. coli during urinary tract infection in humans; and 2) Determine the mechanism of pathogenesis for newly discovered virulence determinants upregulated in E. coli infecting women with urinary tract infection. The expected outcomes of conducting these aims will be a precise assessment of global gene expression and host-specific virulence genes upregulated during infection in women, but not during in vitro culture in urine or rich medium. The positive impact of these studies will be substantial. We will precisely quantify UPEC gene expression during infection of otherwise healthy women. We will determine the mechanisms of action of the newly identified virulence factors active during infection of the urinary tract by E. coli. We will also understand which virulence determinants are both present and expressed during uncomplicated human UTI, and the degree to which they are expressed. Understanding the virulence factors used by the bacterium to colonize the human urinary tract, avoid the immune response, and damage the host will open the door to preventing this public health scourge in women with recurrent UTI and those susceptible to their first UTI.

Public Health Relevance

The proposed research is relevant to public health because urinary tract infection (UTI) remains a significant source of morbidity. Most recently there were 8.2 million physician visits, over 1.7 million emergency room visits, and 366,000 hospitalizations of both men and women in the United States for UTI, at an annual cost of 3.4 billion dollars. These frequencies place UTIs first among kidney and urologic diseases in terms of total cost. This is relevant to NIH's mission because precisely defining the mechanism by which E. coli infects the urinary tract will lead to therapies that may extend healthy life by reducing the burde of these infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094777-08
Application #
9528562
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bavendam, Tamara G
Project Start
2011-09-15
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
8
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
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:
Armbruster, Chelsie E; Mobley, Harry L T; Pearson, Melanie M (2018) Pathogenesis of Proteus mirabilis Infection. EcoSal Plus 8:
Sintsova, Anna; Smith, Sara; Subashchandrabose, Sargurunathan et al. (2018) Role of Ethanolamine Utilization Genes in Host Colonization during Urinary Tract Infection. Infect Immun 86:
Packiriswamy, Nandakumar; Gandy, Jeff; Smith, Sara N et al. (2017) Distinct Signature of Oxylipid Mediators of Inflammation during Infection and Asymptomatic Colonization by E. coli in the Urinary Bladder. Mediators Inflamm 2017:4207928
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:
Mobley, Harry L T (2016) Measuring Escherichia coli Gene Expression during Human Urinary Tract Infections. Pathogens 5:
Subashchandrabose, Sargurunathan; Mobley, Harry L T (2015) Virulence and Fitness Determinants of Uropathogenic Escherichia coli. Microbiol Spectr 3:
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

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