Theclassicsymptomsofinflammation—rubor(red-ness),tumour(swelling),dolor(pain)andcalor(heat)—arethegrossmanifestationsofacomplexbiochemicalefforttoresolveinfectionandregainhomeostasis1.Attheapexofthiscascadearepatternrecognitionreceptors(PRRs),whichhavegermline-encodedspecificitiesforpathogen-associatedmolecularpatterns(PAMPs)anddamage-associatedmolecularpatterns(DAMPs).PRRsatthehostcellsurfaceandinendosomessurveytheextracellularspace2.TheintegrityofplasmamembranesandendosomalmembranesismonitoredbycytosolicandnuclearPRRsthatcontrolpro-inflammatorycaspase-dependentresponses,whichincludethecelldeathpro-grammeofpyroptosisandthereleaseofthecytokinesinterleukin-1β(IL-1β)andIL-18(BOX1).Fivemamma-liancaspasesareclassifiedasinflammatory:caspase1(presentinhumansandmice),caspase4(presentinhumans),caspase5(presentinhumans),caspase11(presentinmice)andcaspase12(non-functionalinmosthumans,andpresentinmice)3.Caspase1,caspase4,caspase5andcaspase11promoteinflam-matoryresponses,whereascaspase12isproposedtodampenthem3.Defectsintheactivationofpro-inflammatorycaspasesandthedownstreamprocessesofpyroptosisandcytokinereleaseareassociatedwithreducedsurvivalandhigherbacterialand/orviralloadsfollowinginfectionwithSalmonellaentericasubsp.entericaserovarTyphimurium,Shigellaflexneri,Yersiniapseudotuberculosis,Francisellatularensis,influ-enzavirus,herpessimplexvirus1,mousecytomegalo-virusandotherpathogens,whichemphasizesacrucialroleforthesepathwaysinhostdefence4,5.Thebreachingofmembranesisessentialtotheviru-lencecycleofmanypathogensandtakesdiverseforms(FIG.1).Somebacteria,suchasSalmonellaspp.,Yersiniaspp.,S.flexneriandLegionellapneumophila,injecteffectorproteinsdirectlyintothehostcellthroughdedicatedsecretionsystems6–9(BOX2).Theseconduitscanfunctionacrosshostplasmamembranesorvacu-olarmembranes,whichenablesextracellularbacteriaandbacteriathatareenclosedinmembrane-boundcompartmentstoaccessthecytosolandaltercrucialbiologicalprocessesinhostcells.Somebacteria,suchasShigellaspp.,Francisellaspp.,...
