Top Banner
TREATMENT AND IMMUNE CONTROL OF MALARIA AND TB Unit 5 Paul Thomas Paul.Thomas@stjude.org Department of Immunology St. Jude Children’s Research Hospital
54

Unit 5 Malaria and TB 2016.ppt · Plasmodium malariae: infrequent cause of clinical malaria, especially in Africa. ... Microsoft PowerPoint - Unit 5 Malaria and TB 2016.ppt ...

Apr 12, 2019

Download

Documents

nguyennga
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript

TREATMENT AND IMMUNE CONTROL OFMALARIA ANDTBUnit5PaulThomasPaul.Thomas@stjude.orgDepartmentofImmunologySt.JudeChildrensResearchHospital

MALARIA PREVALENCE

~350500millioninfections/year

12milliondeaths/year,mostofthemamongchildrenunder5

MALARIA LIFE CYCLE

PLASMODIUM SPP. Inhumans:

Plasmodiumfalciparum:causesthemostsevereformofmalariaandcanbefatal.Cancausechronicinfections(upto23years),butdoesnotformhypnozoites(dormantstagesthatpersistinhepatocytes)anddoesnotrelapse.

Plasmodiumvivax:amajorcauseofclinicalmalaria,butisrarelyfatal.DistributionisrestrictedbytheabsenceofDuffyantigen(whichdeterminesentryintoredbloodcells)inAfricanpopulations.Thisparasiteformshypnozoitesandmightrelapsemanyyearsafterapparentcure.

Plasmodiummalariae:infrequentcauseofclinicalmalaria,especiallyinAfrica.Untreatedinfectionscanpersistaslowgradeparasitaemiaforseveraldecades.

Plasmodiumovale:infrequentcauseofmildmoderateclinicalmalaria,butmightbefoundinmixedinfectionswithotherspecies.Formshypnozoitesandmightrelapse.

Inmice: Plasmodiumchabaudi(P.chabaudichabaudiASandP.chabaudiadami):usedtostudyimmunemechanisms

andimmunoregulationbycytokines,toidentifysusceptibilitylociandtostudytheimmunebasisofpathology.P.chabaudichabaudiAScausesnonlethalinfectioninresistantmousestrainsandlethalinfectioninsusceptiblemousestrains.P.chabaudiadamicausesamild,nonlethalinfection.

Plasmodiumberghei(P.bergheiANKAandP.bergheiK173):widelyusedtostudypathogenesis.P.bergheiANKAservesasamodelofexperimentalcerebralmalaria(ECM);thereisgeneticvariationinthedevelopmentofECMbetweeninbredmousestrains,whichcorrelateswiththeproductionofproinflammatorycytokines.

Plasmodiumyoelii(P.yoelii17XL,P.yoelii17XNLandP.yoeliiYM):usedtostudyimmunemechanismsandpathogenesis,includingECM,asrecombinantmerozoitesurfaceprotein1(MSP1)isavailable.P.yoelii17XLiswidelyusedtoidentifyvaccineinducedimmuneresponses.

Plasmodiumvinckei:P.vinckeivinckei,whichcausesalethalinfection,isusedtostudypathogenesisandforchemotherapystudies;P.vinckeipetteri,whichcausesanonlethalinfection,isusedtostudyimmunemechanisms.

FromNatureReviewsImmunology4,169180(March2004)

PLASMODIUM SPP.: LIFE CYCLE DETERMINE DISEASESEVERITY

Exoerythrocytic schizogony andprepatent andincubationperiods

P.falciparum P.vivax P.ovale P.malariaePrepatentperiod(days) 69 812 1014 1518

Incubationperiod(days) 714 1217 1618 1840Merozoitematuration(days) 57 68 9 1216

Merozoitesproduced 40,000 10,000 15,000 2000

P.FALCIPARUM ALSO CAUSES A MORE SEVEREDISEASE PRESENTATION

Severefeversarecharacteristicofanymalaria,butthefrequencyanddurationofrelapsearethekeyfeaturesoffalciparumandvivaxmalaria

VARIATION OF SYMPTOMS AMONG PLASMODIUMSPECIES DiseaseSeverityandDuration

vivax ovale malariae falciparum

InitialParaoxysmSeverity

moderatetosevere mild

moderatetosevere severe

AverageParasitemia(mm3) 20,000 9,000 6,000

50,000500,000

MaximumParasitemia(mm3) 50,000 30,000 20,000 2,500,000

SymptomDuration(untreated) 38+weeks 23weeks 324weeks 23weeksMaximumInfectionDuration(untreated) 58years

1220months

2050+years

617months

Anemia ++ + ++ ++++Complications renal cerebralModifiedfromMarkell andVoge's MedicalParasitology

Whilefalciparumistheonlyspeciesassociatedwithseveremortality,theothers(particularlyvivax)inflictahighdegreeofmorbidity

Somespeciescanpersistintheliverforyears,whileotherspersistinthebloodstagesasalowlevelinfection

MALARIA IN MICE Earlyduringinfection,P.berghei strainANKAisagoodmodelofcerebral

malaria(CM),andprocessesidentifiedusingthismodelhavebeensubsequentlyvalidatedinhumans.Inbredmousestrainsdiffermarkedlyintheirsusceptibility,showingtheimportanceofhostgeneticvariationinimmunopathogenesis.Similarly,differentstrainsofP.berghei (K173versusANKA)differinsomeaspectsofpathogenesis,indicatingtheinfluenceofparasitegeneticvariationininducedpathology.

InfectionwithP.yoelii strain17XL(alethalstrain)inducesCMthatisassociatedwiththesequestrationofparasitizedredbloodcells,andithasbeenusedtogetherwithP.yoelii strain17XNL(anonlethalstrain)tostudyexperimentalvaccineinducedimmuneresponses.

P.chabaudi chabaudi strainAScausesanonlethalinfectioninresistantmousestrainsandalethalinfectioninsusceptiblemousestrains.Lethality,however,resultsfromhaemolysis thatissecondarytohyperparasitaemia,whichmightnotberelevanttothehumandiseaseprocesses.ThisPlasmodiumstrainhasbeenusedtostudyexperimentalvaccinesandimmunologicalprocessesthatcontrolhyperparasitaemia.InfectionswithP.chabaudi adami areselfresolving,nonpathogenicandnonlethal.

P.vinckei vinckei causesanaggressive,overwhelminghyperparasitaemia.

Immunological processes in malaria pathogenesisLouis Schofield and Georges E. GrauNature Reviews Immunology 5, 722-735 (September 2005)doi:10.1038/nri1686

IMMUNE RESPONSES MEDIATE PLASMODIUMPATHOLOGY

TYPICAL TH1TYPEIMMUNITY CONTRIBUTES TOMALARIA PROTECTION AND PATHOLOGY

Ininfectedmice,antigenispresentedinthespleenwhereTh1cellsregulateinnateandadaptiveimmuneresponses,includingstimulatingantiparasiteantibodyandeffectormechanismssuchasROIandRNI

IMMUNE MECHANISMSTO CONTROL MALARIA Antibodiesblockinvasionofsporozoites

intolivercells Interferon (IFN)andCD8+Tcellsinhibit

parasitedevelopmentinhepatocytes Antibodiesblockinvasionofmerozoites

intoerythrocytes Antibodiespreventsequestrationof

infectederythrocytesbypreventingbindingtoadhesionmoleculesonthevascularendothelium

IFN andCD4+Tcellsactivatemacrophagestophagocytose intraerythrocytic parasitesandfreemerozoites

Antibodiesneutralizeparasiteglycosylphosphatidylinositol andinhibitinductionoftheinflammatorycytokinecascade

Antibodiesmediatecomplementdependentlysis ofextracellulargametes,andpreventfertilizationofgametesandthedevelopmentofzygotes

Mary M. Stevenson & Eleanor M. RileyNature Reviews Immunology 4, 169-180 (March 2004)

FATAL DISEASE IN MALARIA INFECTION

ANTIGENICVARIATION AND SEQUESTRATION:PATHOLOGICAL IMPLICATIONS

PfEMP1variationleadstodistinctwavesofparasitemia

ThisreceptoralsocausesRBCclumpingandsequestrationtoavoidclearanceanddetectioninthespleen

Theseeffectscanbeparticularlydeleteriousintheplacentaandthebrain

DIFFERENT MALARIA SPECIES UTILIZE DIVERSEHOST RECEPTORS

ThestrengthofmalariaasanevolutionarypressurecanbeobservedinWestAfrica,wheremutationstoeliminateexpressionoftheDuffybloodgroupprotectindividualsfromP.vivax

PLATELETS CAN PLAY IMPORTANT IMMUNOLOGICALROLES

PlateletsareactivatedbyTNFandcansecreteotherproinflammatorymediatorssuchasIL1,leadingtoanincreasedlocalinflammationandprovidingadditionalreceptorsfortherecruitmentofparasitizedbloodcells

PATHOLOGYOF CEREBRAL MALARIA

Acascadeofimmunologicalstimulationleadstotheaccumulationofeffectorcelltypesandsystemichypercytokinemia,permebalizingendotheliallayersandcontributingtoblockages

HOST/PARASITE/TREATMENT COMBINETODETERMINE OUTCOME FROM DISEASE

Importanttoconsiderthatonly1/200500infectionsislethal

Themostimportantconsiderationsarelikelytheparasite(onlyfalciparumiscommonlylethal)andimmunity

ANTIMALARIAL DRUGS

RESISTANCE LIMITS DRUG EFFICACY

Eachnewdrugintroductionhasseenarapiddevelopmentandspreadofresistanceworldwide

Mostdrugtargetsareenzymaticallowingparasitemutationtoovercomedrugsensitivity

Chloroquine targetedachemicalprocessresistancedevelopedmoreslowly,butisnowwidespread

EMERGING RESISTANCETOARTEMISININ

Nototalresistancenoted,butincreasedclearancetimesdeveloping

Monotherapiesmaybeonecauseofincreasedresistance(nowbannedinCambodia)

Masstreatmentapproachinheavilyendemicareasalsoconsidered

NEWANDOLDTARGETS OFTHE MEROZOITE STAGE

MolecularcharacterizationofthemerozoiteitselfandtheprocessofRBCinvasionmayprovidenoveltargetsthatwillhopefullyhaveminimalsideeffectsduetotheiruniquestructureandfunction

VECTOR CONTROL

Vectorcontroleffortsrangefrombasicbednets,tosprayinginsecticidesexternallyandonhousewalls,tomoresophisticatedvectorengineeringeffortstoproducemalariaresistantmosquitoes,amongmanyothers

Mathmodelingofinfectiousspreadhasledtosomehypothesesaboutwhichofthesemethodsarethemosteffective(bednets,housewallspraying)andwhichareunlikelytobeeffective(releasingresistantmosquitoes)

MALARIAVACCINETARGETS

Threetypesofvaccineshavebeenproposed,withvariationsineachgroup: Preerthyrocytic vaccines:the

onlytrulysterilizingprotection,buthardtogenerateenoughantibodyimmunity(topreventanyinfection)orCD8immunity(tocleareverysingleinfectedlivercell)

Bloodstagevaccine:designedtoenhanceclearanceofinfectedredbloodcells,therapeuticbutnotsterilizing

Gametocytevaccines:Potentiallystrongantigencandidatesandimmunecomplexescanbecarriedtothemosquitoaltruisticvaccine

RTS,SVACCINEAPPROVED FOR STAGE IIIININFANTS

ThevaccinecandidatefarthestalongisRTS,S,apreerythrocytic vaccineagainstthecircumsporozite protein

Mechanismispresumedtobeantibody,butcellularresponseshavebeenshown

VaccineisadjuvantedandproteinislinkedtohepatitisBantigen

RTS,SSHOWED MODESTEFFICACY IN INFANTS

~30%efficacyshowninlatesttrial

Generallyviewedasdisappointing,butstillmovingforward(previoustrialhad~61%efficacy,butwasmuchsmallerandinadifferenttransmissionarea)

Late 2013 results47% efficacy in children over longer follow up

PrimeboostboostapproachtodriveextraordinarilyhighnumbersofantigenspecificCD8Tcells(1%ofallTcellsneeded)

ThresholdeffectsdemonstratingeffectivesurveillanceofliverstageinfectionbyCD8Tcells Proc Natl Acad Sci U S A. 2008 September

16; 105(37): 1401714022.

CAN CELLULAR RESPONSESWORK AGAINSTINFECTED LIVER CELLS?

MATHMODELING ANDMALARIA

Transmissionmodelshavecontributedsubstantiallytotheunderstandingofmalariacontrol

Withinhostmodelingiscrucialtodeterminethepotentialefficacyofthethreetypesofvaccinecandidates

Thethresholdeffectsofmalariainfection(immunityishelpfulinendemicregions,butrequiresfrequentlowgradereinfection)areparticularlysuitedtoaquantitativeapproach

IMMUNE CONTROL OFMYCOBACTERIUMTUBERCULOSIS

MYCOBACTERIUMTUBERCULOSIS (MTB)

Acidfast,rodshapedbacillus

Uniquewaxrichcellwallcomposedoflongchainfattyacidsandglycolipids

250genesdedicatedtofattyacidmetabolism

Slow,20hourreplicationtime

MTB INFECTIONWORLDWIDE

MTB IMPACT

2.2milliondeaths/year BurdenofdiseasesinDALY(disabilityadjustedlifeyears)

TotalDisabilityAdjustedLifeYears:45million(3.1%). 2billionindividualsinfectedwithM.tuberculosis

10%riskofdevelopingdiseasefollowinginfection Untreated,diseasemortalityis50%

8millionnewtuberculosiscasesperyear(1newcaseevery4seconds)

1015individualsinfectedannuallybyasingleuntreatedpatient

MTB LIFE CYCLE

MTb replicatesinandaccumulatesinmacrophages,mostlyinthelung(thoughothertissuesitesarepossible)

Theaccumulationofinfectedmacrophages,surroundedbyotherleukocytesformsauniquestructurecalledthegranuloma,thecharacteristicfeatureofMTbassociatedlungdamage

MTB LIFE CYCLE PART 2

INNATE RECOGNITIONOF MTB

ACTIVATION OF CYTOKINESTORM Macrophagesdorespondto

theinfection,eveniftheyfailtoclear

Recruitmentofothermonocyte/macrophages/inflammatorycellstothelesion,promotinggranulomaformationandenhancementofcytokinesignaling

Eventuallyrecruitsadaptiveresponsewhichactsthroughtraditionalcellmediatedclearanceandregulationofmacrophageeffectorfunction

ENDOSOMAL/LYSOSOMAL DYSREGULATION

Afteruptakebyscavengerreceptors,MTbarreststhematurationandfusionofthephagosomewiththeendosome

Highlyactivatedmacrophages(IFNgstimulation)cancompletematurationanddestroythebacteriaotherwise,thebacteriaremainlatentorcangrow

PREVENTION OF ACIDIFICATIONLEADSTO PERSISTENCE

MTbusesactiveprocessestopreventacidification

Inertlatexbeadscompletethecycleandarerapidlyacidifiedwithinfiveminutesofuptake

Persistencealsorequiresimportantmetabolicadaptations(lowoxygenenvironment)thatallowcontinuedbacterialgrowthandsurvival

INITIATION OFTHEADAPTIVE RESPONSE

Thecytokinestorminitaitedbytheinnateresponsedeterminesthecharacteroftheensuingadaptiveresponse

NonclassicalTcells(gammadelta,CD1restricted)playanimportantroleinMTbcontrol,butarenotconservedbetweenhumansandmice,makingtheirstudydifficult(onereasonwhyguineapigsareoftenusedinMTb studies)

BothCD4andCD8functions(cytokineregulationanddirectcellclearance)areassociatedwithprotectionfromdisease

GENERATION OFANTIGENSPECIFIC REGULATORYTCELLS

TCELL REGULATION OF MACROPHAGE EFFECTORFUNCTION

Thebalanceofregulatoryvs.effector signals(andthevarioustypesofthosesignals)determinetheactivationmileu ofthegranuloma andtheinfectedmacrophage

Immuneassociatedpathologyisalsoarisk,sosomeregulatorybalanceisrequiredtomaintainthelungphysiologywhileachievingclearanceorcontrol

IL10REGULATION OF LUNG PATHOLOGY

IL10hasbeenshowninmultipleinfectionstobeakeyregulatoryofpathology

Ininfluenza,IL10producedbymultiplecelltypesisrequiredforsurvivalincertainmodelsofinfection

Thepleiotropic effectsofthiscytokinearestillpoorlyunderstoodatamechanisticlevel

CONTROL OF MTB

SUMMARY OF CONTROL MECHANISMS

Phagolysosomal destructionisthemostimportantmechanismforremovingbacteria

IFNg stimulatesthematurationofthephagolysosome,overcomingtheinhibitorysignalsusedbyMTb

ThemosteffectiveformofthiskillinginvolvesROIandRNI

Adaptiveimmunityisimportantforregulatingthecytokineenvironmentand,toasmallerextent,forcytolytickilling

TB incidence rates decrease with recovery of CD4 cell counts during antiretroviral therapy.

Candice K. Kwan, and Joel D. Ernst Clin. Microbiol. Rev. 2011;24:351-376

Estimated excess TB cases attributed to the worsening HIV epidemic in the United States from 1985 to 1992.

Candice K. Kwan, and Joel D. Ernst Clin. Microbiol. Rev. 2011;24:351-376

HUMANGENETIC DEFICIENCIES

TheprimaryphenotypeofindividualswithgeneticsdeficienciesinIFNgsignalingoractivationissusceptibilitytoMycobacterialdisease

Incontrast,deficienciesinTypeIIFNsresultinviralsusceptibilities

WHAT CAUSESREACTIVATION?

Indevelopingcountries,postprimarydiseaseratepeaksinyoungadultagegroups(commonfeatureofseveraltypesofinfectionsendocrineinfluence?)

Immunosuppression ofinnateoradaptiveimmunityresultsinreactivation(HIV,TNFblockade)

Immunesenescence(aging)

RATE OF ADAPTIVE RESPONSE CORRELATESWITHCONTROL

WHAT CONTROLS REACTIVATION?

DiagnosisandassessmentofTBstillreliesonchestradiography

Rapidsequencingapproachesmightprovideaplatformforgreaterdiagnosticdiscernmentwithlessinvasivetechniques

Thesestudiesalsogeneratehypothesesthatcanleadtobetterunderstandingandpredictionofreactivation

SUMMARY AND PERSPECTIVES MTbisnevercompletelyclearedfollowinginitialinfection

Theprimaryeffectormechanismsaremacrophagebactericidalfunctions,buttheirsuccessisdeterminedbythecytokineandcellularregulatoryenvironment

Smallsubtleshiftsovertimeordramaticshorttermchangesleadtoreactivationanddisease