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)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Richardson, Monica L; Fu, Chi-Ling; Pennington, Luke F et al. (2014) A new mouse model for female genital schistosomiasis. PLoS Negl Trop Dis 8:e2825
Hsieh, Yi-Ju; Fu, Chi-Ling; Hsieh, Michael H (2014) Helminth-induced interleukin-4 abrogates invariant natural killer T cell activation-associated clearance of bacterial infection. Infect Immun 82:2087-97
Hsieh, Michael Harrison (2014) The microbiome and probiotics in childhood. Semin Reprod Med 32:23-7
Honeycutt, Jared; Hammam, Olfat; Fu, Chi-Ling et al. (2014) Controversies and challenges in research on urogenital schistosomiasis-associated bladder cancer. Trends Parasitol 30:324-32
Wang, Jing-Hung; Singh, Rachna; Benoit, Michael et al. (2014) Sigma S-dependent antioxidant defense protects stationary-phase Escherichia coli against the bactericidal antibiotic gentamicin. Antimicrob Agents Chemother 58:5964-75
Wu, Jonathan A; Hsieh, Michael H (2014) Robot-assisted laparoscopic hysterectomy, gonadal biopsy, and orchiopexies in an infant with persistent mullerian duct syndrome. Urology 83:915-7
Hsieh, Michael H; Eisenberg, Michael L; Hittelman, Adam B et al. (2012) Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. Hum Reprod 27:1577-80
Fu, Chi-Ling; Odegaard, Justin I; Herbert, De'Broski R et al. (2012) A novel mouse model of Schistosoma haematobium egg-induced immunopathology. PLoS Pathog 8:e1002605
Elliott, Christopher S; Hsieh, Michael H; Sokol, Eric R et al. (2012) Robot-assisted versus open sacrocolpopexy: a cost-minimization analysis. J Urol 187:638-43
Hsieh, Michael H; Alonzo, David G; Gonzales, Edmond T et al. (2011) Ex-premature infant boys with hypospadias are similar in size to age-matched, ex-premature infant boys without hypospadias. J Pediatr Urol 7:543-7

Showing the most recent 10 out of 12 publications