Abstract

Malariaisasignificantglobalhealthprobleminwhichwestillfailtounderstandmany protectivefeaturesoftheimmuneresponse.Naturalkiller(NK)cellsproduce inflammatorycytokinesduringtheearlystagesofinfection,yethavealsobeenshownin viralmodelstolimitTcellandBcellresponses.WerecentlydemonstratedthatNKcell- producedIL-10canlimitCD8+Tcellactivityduringexperimentalcerebralmalariaand therebyrescuemicefromfatal,CD8+Tcell-mediatedimmunopathology.Usingnewly generatedmousestrains,wewillvisualthelocationandcellularinteractionsofNKcells inthebrainandestablishthecellulartargetsofNKcell-derivedIL-10duringcerebral disease.OurstudieswillalsodetermineifdistincthumanNKcellsubsetsaremore efficientatproducingIL-10,andifthesecellscorrelatewithprotectionfrommalaria symptomsinhumans.Finally,wewillinvestigatetheimpactofNKcell-derivedIL-10on thedevelopmentandfunctionofmemoryCD8+Tcells.Ourobjectiveistounderstand howNKcellregulatoryfunctionslikeIL-10productiondecreaseimmunopathologyand symptomaticinfection,andshapethedevelopingTcellresponse.Theproposedwork willdeterminetheconsequencesofNKcell-derivedIL-10duringtheimmuneresponse tomalariaandrevealwaystoexploitregulatoryNKcellfunction,therebyimproving immunityinpopulationsatriskforseveredisease.

Public Health Relevance

Duringmalariainfection,humanscanexperiencebothparasitemediateddiseaseandpathology resultingfromanoverlyrobustimmuneresponse.Thisprojectaimstounderstandhowa rapidlyfunctionalimmunecellcallednaturalkillercells,canparticipateinbothpathogen controlandinlimitinginflammatoryresponses.Ourgoalistounderstandthesignificanceof naturalkillercellsduringmalariainfection,anddeterminestrategiesforenhancingresponses thatprotectpeoplefromsymptomaticdisease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI143828-03
Application #
10092095
Study Section
Immunity and Host Defense (IHD)
Program Officer
Pesce, John T
Project Start
2019-02-08
Project End
2024-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455