Dentalcariesisthemostprevalentchronicdiseaseinbothchildrenandadults,affecting80?90%ofthe worldpopulation3.4.Thebacterium,Streptococcusmutans,istheprimarycausativeagentofthisdiseaseandis frequentlyfoundtogetherwithStreptococcussobrinusinsituationsofmoreseveredentalcaries12,18,19.While manyofthevirulencefactorscontributingtothecariogenictyofS.mutanshavebeenwellstudied,the mechanismsthatregulatevirulencegeneexpressionhasreceivedlessattention.Understandingthe mechanismsbywhichS.mutansregulatesitsvirulencearecriticalfordevelopingtherapeuticapproachesto mitigatedentalcaries.Manybacteria,includingstreptococci,areknowntoregulategeneexpressionthrougha cell-to-cellcommunicationmechanismcalledquorumsensing(QS)21.Previousworkbyourlabhas demonstratedthatRgg-typeQSpathwaysregulatebiofilmformationandvirulenceexpressionin StreptococcuspyogenesandgeneticcompetenceinS.mutans26,35.WehaveidentifiedadditionalRgg pathwaysinS.mutansandourpreliminarydatahasidentifiedputativevirulencegenescontrolledbyeachRgg therebyprovidinginsightonthebiologicalfunctionofRggQScircuits.Moreover,thevirulenceofS.mutans mayalsobeinfluencedthroughinteractionswithS.sobrinus.Thecurrentproposalwillexplorethe mechanismsbywhichS.mutansregulatesgeneexpressionaloneandinthepresenceofS.sobrinus.The centralhypothesisofthisproposalisthatvirulencegeneexpressionbyS.mutansismodulated throughRgg-mediatedQSpathwaysandthroughitsinteractionwithS.sobrinus.
The specificaims of thisresearchare(1)DescriberegulatoryfunctionandchemicalsignalingforRggparalogsinS.mutans.(2) CharacterizethesynergisticeffectsofS.mutansandS.sobrinusinteraction.Toelucidatethefunctionalroles ofeachRggregulon,wewillperformaseriesofphenotypicexperiments,eachofwhichexploitsavirulence traitsuggestedbyourpreliminarydata,onrggdeletionmutants.Wewillthenanalyzethegenome-wide expressionprofileofeachmutantusingRNA-seqtodeterminegenenetworksunderpinningthephenotypes observedandtoidentifyadditionaltranscriptionaltargetsofeachRgg.TheinfluenceofS.sobrinusonS. mutans?geneexpressionwillalsobeassessed.WewillpreformRNA-seqondual-speciesbiofilmsofS. mutansandS.sobrinustodeterminetheinfluenceofthisinteractionongeneexpression.Geneticpathways showingdifferentialexpressionwillbetopcandidatesthatcontributetointerspeciesinteraction,andmutantsof thesepathwayswillbegeneratedandtestedfortheircontributiontovirulence.Itisanticipatedthatthis researchwilldelineatecriticalaspectsofS.mutanspathogenesisthatwillhelpimprovestrategiesof preventionandtreatmentofdentalcaries.Thisresearchisalsoanimportantstepinachievingthelong-term goalofdefiningtheintra-andinterspeciesQSmechanismsthatmodulatevirulenceinS.mutans,andhow theseprocessescontributetodiseasepathogenesis.

Public Health Relevance

Dentalcaries,otherwiseknownastoothdecay,isacommonchronicinfectiousdiseaseaffectingmuch oftheglobalpopulation.Thebacteria,StreptococcusmutansandStreptococcussobrinus,arecommonly foundtogetherandarelargelyresponsibleforcausingthisdisease.S.mutanspopulationsareableto coordinategeneexpressionviaabacterialcell-cellcommunicationsystemtermedquorumsensing(QS).We hypothesizethataQSsystemidentifiedinourlabplaysacentralroleintheabilityofS.mutanstointeractwith S.sobrinusandcausedisease.ThedisruptionofthisQSsystemhasthepotentialtoattenuatethisbacterium sothatitislessabletocausedentalcaries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DE026051-04
Application #
9748340
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Frieden, Leslie A
Project Start
2016-09-16
Project End
2021-03-15
Budget Start
2019-09-16
Budget End
2020-03-15
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612