Genitourinary infections affect children and adults worldwide. Gut-derived or sexually or vertically transmitted pathogens travel through the vagina to infect the female genitourinary tract. However, commensal Lactobacillus biofilms may prime genitourinary epithelial cells for anti-pathogenic responses by regulating genes which participate in natural killer T (NKT) cell activity, such as interferon gamma (IFNG) receptor 1 and the bacterial lipid antigen-presenting molecule CD1d. In turn, the formation of vaginal Lactobacillus biofilms may depend on estrogen-induced, epithelial production of glycogen, a food source for commensal-derived probiotics, """"""""live microorganisms which when administered in adequate amounts confer a health benefit on the host"""""""". We hypothesize that estrogen stimulation of glycogen production by genitourinary epithelium promotes stability of probiotic Lactobacillus biofilms, which reciprocally modulate epithelial CD1d-mediated, IFNG-associated NKT cell responses to pathogens. This hypothesis will be tested through the following aims:
Aim 1, elucidate the effects of estrogen-induced glycogen on biofilms associated with genitourinary epithelial cells;
Aim 2, investigate the in vivo and in vitro mechanisms of probiotic-mediated, NKT cell interactions with genitourinary epithelium;
and Aim 3, clarify the microecologic role of estrogen, genitourinary epithelial, and NKT cell interactions in shaping the genitourinary microbiome. Through these studies, the candidate seeks to become a physician investigator by complementing his background in pediatric urology and graduate work in adaptive immunology with training in biofilm microbiology and innate immunology. During the early portion of the candidate's career, the candidate will build on his foundation as a physician scientist through grantsmanship workshops;strong mentorship by experts in biofilm biology, innate immunity, and pediatric urology;scientific collaborations;practical experience;and didactic coursework that focuses on biofilms, innate immunity, and genitourinary biology. In summary, this project will lay the groundwork for a successful career as an independent investigator and will lead to the identification of novel pathways by which estrogen and probiotics protect the female genitourinary tract from infections.

Public Health Relevance

Biofilms of commensal vaginal bacteria may have probiotic (beneficial) properties which prime the genitourinary tract for natural killer T cell responses against infections. This proposal will examine how these biofilms grow on genitourinary epithelium, and how probiotics, estrogen, genitourinary epithelium, and natural killer T cells interact to determine which bacteria grow in the female genitourinary tract.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Rankin, Tracy L
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Stanford University
Schools of Medicine
United States
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Silveira, Alda Maria Soares; Costa, Emanuele Gama Dutra; Ray, Debalina et al. (2016) Evaluation of the CCA Immuno-Chromatographic Test to Diagnose Schistosoma mansoni in Minas Gerais State, Brazil. PLoS Negl Trop Dis 10:e0004357
Banskota, Nirad; Odegaard, Justin I; Rinaldi, Gabriel et al. (2016) Computational deconvolution of gene expression by individual host cellular subsets from microarray analyses of complex, parasite-infected whole tissues. Int J Parasitol 46:447-52
Xiao, Yuan; Lu, Yi; Hsieh, Michael et al. (2016) A Microfiltration Device for Urogenital Schistosomiasis Diagnostics. PLoS One 11:e0154640
Hsieh, Michael H; Mentink-Kane, Margaret M (2016) Smallpox and Dracunculiasis: The Scientific Value of Infectious Diseases That Have Been Eradicated or Targeted for Eradication. Is Schistosomiasis Next? PLoS Pathog 12:e1005298
Mach, Kathleen E; Mohan, Ruchika; Patel, Shailja et al. (2015) Development of a Biosensor-Based Rapid Urine Test for Detection of Urogenital Schistosomiasis. PLoS Negl Trop Dis 9:e0003845
Conti, Simon L; Honeycutt, Jared; Odegaard, Justin I et al. (2015) Alterations in DNA methylation may be the key to early detection and treatment of schistosomal bladder cancer. PLoS Negl Trop Dis 9:e0003696
Rinaldi, Gabriel; Young, Neil D; Honeycutt, Jared D et al. (2015) New research tools for urogenital schistosomiasis. J Infect Dis 211:861-9
Fu, Chi-Ling; Odegaard, Justin I; Hsieh, Michael H (2015) Macrophages are required for host survival in experimental urogenital schistosomiasis. FASEB J 29:193-207
Santoro, Jonathan D; Chao, Stephanie; Hsieh, Michael H et al. (2015) Multimodality Renal Failure in a Patient with OEIS Complex. AJP Rep 5:e161-4
Huth, Markus E; Han, Kyu-Hee; Sotoudeh, Kayvon et al. (2015) Designer aminoglycosides prevent cochlear hair cell loss and hearing loss. J Clin Invest 125:583-92

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