A Pseudomonas aeruginosa hepta‐acylated lipid A variant associated with cystic fibrosis selectively activates human neutrophils

[摘要] Pseudomonasaeruginosa(PA)infectionincysticfibrosis(CF)lungdiseasecausesairwayneutrophiliaandhyperinflammationwithouteffectivebacterialclearance.WeevaluatedtheimmunostimulatoryactivitiesoflipidA,themembraneanchorofLPS,isolatedfrommutantsofPAthatsynthesizestructuralvariants,presentintheairwaysofpatientswithCF,todetermineiftheycorrelatewithdiseaseseverityandprogression.InasubsetofpatientswithaseverelatestageofCFdisease,auniquehepta‐acylatedlipidA,hepta‐1855,issynthesized.Inprimaryhumancellcultures,wefoundthathepta‐1855functionedasapotentTLR4agonistbyprimingneutrophilrespiratoryburstandstimulatingstrongIL‐8frommonocytesandneutrophils.hepta‐1855alsohadapotentsurvivaleffectonneutrophils.However,itwaslessefficientinstimulatingneutrophilgranuleexocytosisandalsolesspotentintriggeringproinflammatoryTNF‐αresponsefrommonocytes.InPAisolatesthatdonotsynthesizehepta‐1855,adistinctCF‐specificadaptationfavorssynthesisofapenta‐1447andhexa‐1685LPSmixture.Wefoundthatpenta‐1447lackedimmunostimulatoryactivitybutinterferedwithinflammatoryIL‐8synthesisinresponsetohexa‐1685.Together,theseobservationssuggestapotentialcontributionofhepta‐1855tomaintenanceoftheinflammatoryburdeninlate‐stageCFbyrecruitingneutrophilsviaIL‐8andpromotingtheirsurvival,aneffectpresumablyamplifiedbytheabsenceofpenta‐1447.Moreover,therelativeinefficiencyofhepta‐1855intriggeringneutrophildegranulationmaypartlyexplainthepersistenceofPAinCFdisease,despiteextensiveairwayneutrophilia...

[学科分类] 生理学

[关键词] immunoevasion;TLR4;inflammation;chronic infection