Pathogenesis of mucosal infections are often studied in monomicrobial settings that ignore the possible influence of other potentially pathogenic microbial flora present at the time of exposure. Urinary tract infection (UTI) is a common and sometimes persistent disease that can have life-threatening outcomes in susceptible populations. Women are at much higher risk of UTI than men, and are more likely to experience complications of infection during particular stages of the reproductive lifespan -- in pregnancy and after menopause. Abundant and diverse microbial populations exist in periurethral and nearby mucosal sites, therefore there is a high likelihood that bacterial exposures of the urinary tract are often polymicrobial. Uropathogenic E. coli (UPEC) is the most common cause of UTI, but often co-occurs with low levels of Gram positive bacteria in urine in a polymicrobial context. The presence of sub-diagnostic levels of Gram positives in urine is usually considered clinically insignificant;however, this assumption has never been tested experimentally. Group B Streptococcus (GBS) in a common commensal of the lower gastrointestinal and vaginal tracts and is commonly isolated from women with UPEC UTI or asymptomatic bacteriuria. This proposal describes the development of a novel murine model to study polymicrobial-host interactions in the urinary tract in mice. Proposed experiments use this model to investigste the impact of GBS on UPEC UTI outcomes. Preliminary data show that GBS has a striking impact on UPEC infection, altering the course, severity, and outcome of UTI. Ongoing cellular and molecular studies are defining specific host and bacterial factors involved in the polymicrobial dialogue. In this proposal, we aim to more fully understand the mechanisms driving alterations to the UPEC pathogenic cascade upon polymicrobial inoculation with GBS. In addition to paradigm-shifting implications for urinary pathogenesis, the proposed studies may uncover valuable predictors of risk in particular clinical settings.

Public Health Relevance

Urinary tract infection (UTI) caused by uropathogenic E. coli (UPEC) is a major public health problem. We have developed an aged multiparous mouse model to study the impact of polymicrobial urinary tract exposure on the development of ascending and systemic infection caused by UPEC. Mechanistic insights about the role of Group B Streptococcus (GBS) in the exacerbation of UPEC infection will lay the foundation for a better clinical understanding of microbial risk factors for the development complicated UTI in susceptible groups.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (UGPP)
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Mullins, Christopher V
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Washington University
Schools of Medicine
Saint Louis
United States
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Gilbert, Nicole M; O'Brien, Valerie P; Lewis, Amanda L (2017) Transient microbiota exposures activate dormant Escherichia coli infection in the bladder and drive severe outcomes of recurrent disease. PLoS Pathog 13:e1006238
Weimer, Cory M; Deitzler, Grace E; Robinson, Lloyd S et al. (2016) Genome Sequences of 12 Bacterial Isolates Obtained from the Urine of Pregnant Women. Genome Announc 4:
Kline, Kimberly A; Lewis, Amanda L (2016) Gram-Positive Uropathogens, Polymicrobial Urinary Tract Infection, and the Emerging Microbiota of the Urinary Tract. Microbiol Spectr 4:
Kline, Kimberly A; Schwartz, Drew J; Gilbert, Nicole M et al. (2014) Impact of host age and parity on susceptibility to severe urinary tract infection in a murine model. PLoS One 9:e97798
Gilbert, Nicole M; O'Brien, Valerie P; Hultgren, Scott et al. (2013) Urinary tract infection as a preventable cause of pregnancy complications: opportunities, challenges, and a global call to action. Glob Adv Health Med 2:59-69
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