ProgrammedcelldeathasadefenceagainstinfectionIneJorgensen,ManiraRayamajhi,andEdwardA.MiaoDepartmentofMicrobiologyandImmunology,LinebergerComprehensiveCancerCenter,andCenterforGastrointestinalBiologyandDisease,UniversityofNorthCarolinaatChapelHill,ChapelHill,NC27599,USAAbstractEukaryoticcellscandiefromphysicaltrauma,resultinginnecrosis.Alternately,theycandieviaprogrammedcelldeathuponstimulationofspecificsignallingpathways.Herewediscusstheutilityoffourcelldeathpathwaysininnateimmunedefenceagainstbacterialandviralinfection:apoptosis,necroptosis,pyroptosisandNETosis.Wedescribetheinteractionsthatinterweavedifferentprogrammedcelldeathpathways,whichcreatecomplexsignallingnetworksthatcross-guardeachotherintheevolutionaryarmsracewithpathogens.Finally,wedescribehowtheresultingcellcorpses—apoptoticbodies,pore-inducedintracellulartraps(PITs)andneutrophilextracellulartraps(NETs)—promoteclearanceofinfection.CorrespondencetoE.A.M.emiao@med.unc.edu.HighlightedReferences21,22DiscoveryofGSDMDastheeffectorofpyroptosiscleavedbycaspase-1and-1126,28GSDMDformsaporeinmembranes.39InvivoimportanceofNKcytotoxicityasaparalleleffectormechanismtopyroptosisinclearingintracellularniches.19Invivoimportanceofcaspase-11indefenseagainstcytosol-invasivebacteria9Firstdemonstrationthatpyroptosisisaninnateimmuneeffectormechanisminvivo.52ZBP1detectsMCMVtotriggernecroptosis,butiscounteractedbyMCMVvIRA.69Ripk3−/−micearesusceptibletoHSV-1infection56RIPK3criticalfornecroptosisandRipk3−/−micesusceptibletovacciniainfection.60–62MLKLpermeabilizesmembranes.85,86cGASasguardforMOMP/caspase-9,triggeringatypeIIFNresponsewhenapoptosisfailstocomplete.88,89TheembryoniclethalityofCasp8−/−miceiscomplementedbycrossingwithRipk3−/−,demonstratingthatnecroptosisguardscaspase-8.100DescriptionoftheeffectofCasp8−/−mutationuponTLR3signallingandNLRP3priming.134EfferocytosisasaneffectormechanismagainstM.tuberculosis.101Discoveryofneutrophilextracellulartraps(NETs).106EvidenceofvitalNETosis,whereinneutrophilsformNETsbu...
