title: Innate transcriptional networks activated in bladder in response to uropathogenic Escherichia coli drive diverse biological pathways and rapid synthesis of IL-10 for defense against bacterial urinary tract infection.
abstract: Early transcriptional activation events that occur in bladder immediately following bacterial urinary tract infection (UTI) are not well defined. In this study, we describe the whole bladder transcriptome of uropathogenic Escherichia coli (UPEC) cystitis in mice using genome-wide expression profiling to define the transcriptome of innate immune activation stemming from UPEC colonization of the bladder. Bladder RNA from female C57BL/6 mice, analyzed using 1.0 ST-Affymetrix microarrays, revealed extensive activation of diverse sets of innate immune response genes, including those that encode multiple IL-family members, receptors, metabolic regulators, MAPK activators, and lymphocyte signaling molecules. These were among 1564 genes differentially regulated at 2 h postinfection, highlighting a rapid and broad innate immune response to bladder colonization. Integrative systems-level analyses using InnateDB (http://www.innatedb.com) bioinformatics and ingenuity pathway analysis identified multiple distinct biological pathways in the bladder transcriptome with extensive involvement of lymphocyte signaling, cell cycle alterations, cytoskeletal, and metabolic changes. A key regulator of IL activity identified in the transcriptome was IL-10, which was analyzed functionally to reveal marked exacerbation of cystitis in IL-10-deficient mice. Studies of clinical UTI revealed significantly elevated urinary IL-10 in patients with UPEC cystitis, indicating a role for IL-10 in the innate response to human UTI. The whole bladder transcriptome presented in this work provides new insight into the diversity of innate factors that determine UTI on a genome-wide scale and will be valuable for further data mining. Identification of protective roles for other elements in the transcriptome will provide critical new insight into the complex cascade of events that underpin UTI.
authors.affiliation: School of Medical Sciences, Centre for Medicine and Oral Health, Griffith University Gold Coast Campus, Queensland 4222, Australia.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Duell
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Carey
authors.forename: Chee K
authors.initials: CK
authors.lastname: Tan
authors.forename: Xiangqin
authors.initials: X
authors.lastname: Cui
authors.forename: Richard I
authors.initials: RI
authors.lastname: Webb
authors.forename: Makrina
authors.initials: M
authors.lastname: Totsika
authors.forename: Mark A
authors.initials: MA
authors.lastname: Schembri
authors.forename: Petra
authors.initials: P
authors.lastname: Derrington
authors.forename: Helen
authors.initials: H
authors.lastname: Irving-Rodgers
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brooks
authors.forename: Allan W
authors.initials: AW
authors.lastname: Cripps
authors.forename: Michael
authors.initials: M
authors.lastname: Crowley
authors.forename: Glen C
authors.initials: GC
authors.lastname: Ulett
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D003556:Cystitis / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D036781:Fimbriae Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000097:blood / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D059467:Transcriptome / Q000235:genetics / Q000276:immunology*; D020298:U937 Cells; D056689:Uropathogenic Escherichia coli / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D019459:Urothelium / Q000276:immunology / Q000382:microbiology / Q000473:pathology
chemical_list: C508609:IL10 protein, human; C556062:IL10 protein, mouse; C063055:fimbrillin; D016753:Interleukin-10; D036781:Fimbriae Proteins