SinceamajorcomplicationofUTIsisfrequentrecurrence,thereappearstobeafatefuldefect intheurinaryimmunesystem.Adistinctfeatureofthebladderwhichappearstocontributeto theirsusceptibilitytoreinfectionisthehighdegreeofatypicaltissueremodelingthatoccurs followingeachinfection,predisposingthebladdertofutureinfections.Sinceverylittleis currentlyknownregardingbladderremodeling,studiesonthistopicmayrevealnewstrategies tocombatrecurrentUTIs.Wehavehypothesizedthatbecauseofthehighlycytotoxicand hyperosmolarnatureofurine,thebladderinitiatesavigorousre-epithelizationandremodeling programtorapidlyrecoverlostepitheliumaftereachinfection.Ourpreliminarystudieshave validatedthisnotionandrevealedthatTcellsrecruitedintothebladderaremorespecializedin directingtissuerepair(Th2)thaninpathogenelimination(Th1).Consequently,theinfecting bacteriainthebladderarenotcompletelyeliminatedfollowingresolutionofinfection, predisposingthisorgantofutureflare-ups.SincethetissuerepairTcellsrecruitedintothe bladdertendtopersistandcouldbequicklyevokedwithreinfection,themagnitudeofthe remodelingprogramishigh,significantlyimpactingbladdervoidingcapacity.Wehavefound thatacriticalimmuneregulatorassociatedwiththebladderrepairprogramisadistinctsubclass ofdendriticcells(DCs),whichmovesintothesubepithelialregionofthebladdersoonafterthe lossofthesuperficialepithelium.Here,weproposetodeterminethespecificroleofthisDC subclassinepithelialrepair.WewillalsoexaminetheunderlyingbasisfortheTh2biasofT cellsrecruitedintothebladderfollowingboutsofinfection.Finally,wewillinvestigatethe possibilityofreprogramingTh2primedbladderresponseintoaTh1typeresponseby immunizingnaveandchronicallyinfectedmicewithavaccineantigenco-administeredwithTh1 biasingadjuvant.Wesuspectthatsuchvaccineswillnotonlyprotectbladderfromfuture infectionbutalsopermitrecoveryofbladderfunctioninthesemice

Public Health Relevance

Statement: A distinct feature of the bladder is its increased susceptibility to reinfection which appears to grow with each infection. We have attributed this phenomenon to preferential recruitment into the bladder of cells specialized in tissue repair over cells that are capable of eliminating pathogens, which leaves this organ prone to reinfection. Our goal here is to examine the basis for this aberrant response and to device a preventive vaccination strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK121032-01
Application #
9713011
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mullins, Christopher V
Project Start
2019-05-20
Project End
2023-03-31
Budget Start
2019-05-20
Budget End
2020-03-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705