Melanie Yarbrough (Presenter)
Washington University School of Medicine
Bio: Melanie Yarbrough is currently a fellow in the Medical and Public Health Microbiology training program at Washington University School of Medicine in Saint Louis, Missouri. She received her PhD in Molecular Microbiology from the University of Texas Southwestern Medical Center and completed a postdoctoral fellowship in Clinical Chemistry in the COMACC-approved training program at Washington University. Her primary research interest is the discovery and development of biomarkers for infectious diseases such as catheter-associated urinary tract infections.
Authorship: Melanie L. Yarbrough (1), Kristin M. Tiemann (1), John V. Mitsios (2), Cindy Terrill (1), Annette Weindel (1), Dennis J. Dietzen (1), David A. Hunstad (1)
(1) Washington University School of Medicine, Saint Louis, MO (2) Weill Cornell Medine, New York, NY
| Short Abstract Tryptophan (Trp) catabolism yields kynurenine metabolites through the activity of indoleamine-2,3-dioxygenase (IDO). The ratio of the product kynurenine (Kyn) to the substrate Trp is used as a surrogate for biological IDO enzyme activity. IDO expression is locally induced during urinary tract infection (UTI) to suppress immunity and facilitate bacterial colonization. We developed a tandem mass spectrometry assay to measure Trp and Kyn in biological samples and compared Kyn/Trp ratios in urine samples of healthy controls to symptomatic patients with and without UTI. Kyn/Trp ratios were non-specifically increased in symptomatic patients versus healthy controls. No difference was seen between symptomatic patients with and without UTI, indicating that Kyn/Trp ratios may serve as a general indicator of a systemic inflammatory process. |
Long Abstract
Tryptophan (Trp) catabolism is implicated in the immunologic balance between responsiveness to pathogens and tolerance to harmless antigens. The enzyme indoleamine-2,3-dioxygenase (IDO) catalyzes the rate-limiting step in a major Trp catabolism pathway, yielding a number of kynurenine metabolites. IDO expression is induced by inflammatory cytokines in multiple cell types. The ratio of the product kynurenine (Kyn) to the substrate Trp in serum has been used as a surrogate for biological IDO enzyme activity and is elevated in patients with acute kidney transplant rejection, advanced HIV infection, and certain gynecologic cancers. Our research has shown that uropathogenic Escherichia coli (UPEC), the most common cause of of urinary tract infections (UTI), induces IDO expression in bladder epithelial cells during infection. Induction of IDO leads to suppression of innate immune responses, which facilitates establishment of bacterial colonization. Therefore, we reasoned that measurement of Kyn/Trp ratio in patients with UTI may serve as a specific marker of infection. We developed a rapid flow injection tandem mass spectrometry assay to measure both Trp and Kyn in biological samples; this method was accurate and precise in both serum and urine. To test the ability of the Kyn/Trp ratio to predict UTI, we measured Trp and Kyn in three groups of pediatric patients: those with symptomatic, laboratory-confirmed UTI (n=35), those ill with acute conditions other than UTI (n=35), and healthy controls (n=15). Measurement of urinary Kyn and Trp concentrations demonstrated that the Kyn/Trp ratio was elevated in patients with UTI compared to healthy controls (p < 0.001). However, the Kyn/Trp ratio was also elevated in symptomatic patients without UTI compared to healthy controls (p < 0.001). Notably, there was no significant difference between symptomatic patients with and without UTI (p = 0.84), indicating that urinary Kyn/Trp ratio is not specific as a biomarker for UTI but may serve as a more general indicator of a systemic inflammatory process.
References & Acknowledgements:
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