Featured Publications
PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
Xu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 2023, 619: 819-827. PMID: 37438530, PMCID: PMC10371867, DOI: 10.1038/s41586-023-06322-y.Peer-Reviewed Original ResearchConceptsC-terminal β-barrel domainSpike-mediated fusionCell-autonomous defenseLarge-scale exome sequencingΒ-barrel domainGenome-wide CRISPRSARS-CoV-2 infectionHost cell cytosolScramblase activityPhospholipid scramblaseLive SARS-CoV-2 infectionHuman lung epitheliumPLSCR1SARS-CoV-2 USASingle-molecule switchingSARS-CoV-2 variantsExome sequencingHuman populationRestriction factorsViral RNANew SARS-CoV-2 variantsSARS-CoV-2Robust activityLung epitheliumDefense factorsGuanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms
Wandel MP, Kim BH, Park ES, Boyle KB, Nayak K, Lagrange B, Herod A, Henry T, Zilbauer M, Rohde J, MacMicking JD, Randow F. Guanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms. Nature Immunology 2020, 21: 880-891. PMID: 32541830, PMCID: PMC7381384, DOI: 10.1038/s41590-020-0697-2.Peer-Reviewed Original ResearchConceptsGuanylate-binding proteinsCaspase-4 activationCaspase-4Human caspase-4Pyroptotic cell deathGram-negative bacteriaCytosolic bacteriaReplicative nicheEvolutionary evidenceIntracellular bacteriaCell deathMultiple antagonistsNeighboring cellsCaspase-11BacteriaAntibacterial defenseBacterial challengeGasderminShigella flexneriProteinDependent pyroptosisActivationPathwayBacterial lipopolysaccharideGBP2Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease
Tretina K, Park ES, Maminska A, MacMicking JD. Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease. Journal Of Experimental Medicine 2019, 216: 482-500. PMID: 30755454, PMCID: PMC6400534, DOI: 10.1084/jem.20182031.Peer-Reviewed Original ResearchConceptsGuanylate-binding proteinsNumerous host cell typesHost cell typesImportant human diseasesCritical rheostatBasic biologyMicrobial pathogensHost defense activitiesHuman diseasesSimilar functionsCell typesHomeostatic settingsGTPasesInnate immunityDefense activitiesHost defenseInflammatory syndromeNeoplastic diseaseClinical approachTissue damageBacterial infectionsCentral orchestratorDiseaseIFNRheostatInterferon-induced guanylate-binding proteins in inflammasome activation and host defense
Kim BH, Chee JD, Bradfield CJ, Park ES, Kumar P, MacMicking JD. Interferon-induced guanylate-binding proteins in inflammasome activation and host defense. Nature Immunology 2016, 17: 481-489. PMID: 27092805, PMCID: PMC4961213, DOI: 10.1038/ni.3440.Peer-Reviewed Original ResearchIFN-Inducible GTPases in Host Cell Defense
Kim BH, Shenoy AR, Kumar P, Bradfield CJ, MacMicking JD. IFN-Inducible GTPases in Host Cell Defense. Cell Host & Microbe 2012, 12: 432-444. PMID: 23084913, PMCID: PMC3490204, DOI: 10.1016/j.chom.2012.09.007.Peer-Reviewed Original ResearchConceptsGuanylate binding proteinsIFN-inducible GTPasesHuman genome-wide association studiesProtein complex assemblyGenome-wide association studiesPathogen-containing vacuolesHost cell defenseVesicular trafficTranscriptional profilingComplex assemblyCell defenseCell-intrinsic responsesAssociation studiesGTPasesBinding proteinCell interiorIndividual cellsAltered expressionGTPase MDiverse groupCentral roleAutophagicCytosolSpeciesPlantsInterferon-inducible effector mechanisms in cell-autonomous immunity
MacMicking JD. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nature Reviews Immunology 2012, 12: 367-382. PMID: 22531325, PMCID: PMC4150610, DOI: 10.1038/nri3210.Peer-Reviewed Original ResearchConceptsCell-autonomous immunityIndividual host cellsHigher organismsVertebrate cellsEffector proteinsIFN-inducible proteinsAutophagic machineryViral life cycleNew proteinsIntracellular distancesGene programMicrobial replicationCapsid assemblyEssential amino acidsMicrobial pathogensHost cellsIntracellular bacteriaIndividual bacteriaKey PointsAtInnate immune systemAmino acidsInterferon familyVariety of mechanismsProteinPathogen classesGBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals
Shenoy AR, Wellington DA, Kumar P, Kassa H, Booth CJ, Cresswell P, MacMicking JD. GBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals. Science 2012, 336: 481-485. PMID: 22461501, DOI: 10.1126/science.1217141.Peer-Reviewed Original ResearchMeSH KeywordsAlum CompoundsAnimalsApoptosis Regulatory ProteinsCARD Signaling Adaptor ProteinsCarrier ProteinsCaspase 1Cell LineCytoskeletal ProteinsGTP-Binding ProteinsHumansInflammasomesInterferon-gammaInterleukin-1betaLipopolysaccharidesListeria monocytogenesListeriosisMacrophagesMiceNLR Family, Pyrin Domain-Containing 3 ProteinProtein MultimerizationRNA InterferenceSalmonella typhimuriumUric AcidConceptsGuanylate binding protein 5IL-1β/ILImpaired host defensePresence of infectionNLRP3 inflammasome activationCaspase-1 cleavageNLRP3 inflammasome responseNLRP3 inflammasome assemblyInflammasome assemblyBinding protein 5Inflammatory responseInflammasome activationImmune systemTissue damageInflammasome responseHost defenseInflammasome complexCaspase-1Sensory complexProtein 5InflammasomePathogenic bacteriaILInterleukinNLRA Family of IFN-γ–Inducible 65-kD GTPases Protects Against Bacterial Infection
Kim BH, Shenoy AR, Kumar P, Das R, Tiwari S, MacMicking JD. A Family of IFN-γ–Inducible 65-kD GTPases Protects Against Bacterial Infection. Science 2011, 332: 717-721. PMID: 21551061, DOI: 10.1126/science.1201711.Peer-Reviewed Original ResearchConceptsProtein gene familyCell-autonomous immunityMammalian host defenseHost defense proteinsGene-deficient animalsGene familyAutophagy effectorsDefense proteinsHuman genomeGuanosine triphosphataseHost genesComplete mouseIntracellular bacteriaPhagocyte oxidaseIntracellular pathogensPotent oxidativeAntimicrobial peptidesTrafficking programsHost defenseGenomeFunction analysisFamilyGBP1GenesGBP7Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47
MacMicking JD, Taylor GA, McKinney JD. Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47. Science 2003, 302: 654-659. PMID: 14576437, DOI: 10.1126/science.1088063.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedComputational BiologyDisease SusceptibilityFemaleGTP PhosphohydrolasesGTP-Binding ProteinsHydrogen-Ion ConcentrationImmunity, InnateInterferon-gammaMacrophage ActivationMacrophagesMacrophages, AlveolarMaleMiceMice, Inbred C57BLMutationMycobacterium tuberculosisNitric Oxide SynthaseNitric Oxide Synthase Type IIOligonucleotide Array Sequence AnalysisPhagosomesReverse Transcriptase Polymerase Chain ReactionSignal TransductionTuberculosisConceptsNitric oxide synthase 2LRG-47Principal effector mechanismDefective bacterial killingImmune controlEffector mechanismsMtb replicationImpaired maturationBacterial killingIntracellular pathogensMycobacterium tuberculosisHost macrophagesInfected host macrophagesSynthase 2TuberculosisIRG-47MtbIFNDiseaseMiceMacrophagesIdentification of nitric oxide synthase as a protective locus against tuberculosis
MacMicking J, North R, LaCourse R, Mudgett J, Shah S, Nathan C. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 5243-5248. PMID: 9144222, PMCID: PMC24663, DOI: 10.1073/pnas.94.10.5243.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsCarrier ProteinsCation Transport ProteinsCrosses, GeneticDisease SusceptibilityExonsFemaleGenotypeGlucocorticoidsHaplotypesHeterozygoteHomozygoteImmunity, InnateImmunosuppression TherapyIsoenzymesLungMaleMembrane ProteinsMiceMice, Inbred C57BLMice, Inbred StrainsMice, KnockoutMycobacterium tuberculosisNitric Oxide SynthasePolymerase Chain ReactionPolymorphism, GeneticTuberculosisConceptsNitric oxide synthaseOxide synthasePrimary Mycobacterium tuberculosis infectionInducible nitric oxide synthaseHigh-dose glucocorticoidsMycobacterium tuberculosis infectionWild-type miceWild-type littermatesHost immune systemChronic tuberculosisTuberculosis infectionImmune systemCritical host genesTuberculosisMycobacterium tuberculosisProtective genesMiceProtective locusNOS2Host genesSuch pathwaysResponse pathwaysSynthaseGlucocorticoidsLungNITRIC OXIDE AND MACROPHAGE FUNCTION
MacMicking J, Xie Q, Nathan C. NITRIC OXIDE AND MACROPHAGE FUNCTION. Annual Review Of Immunology 1997, 15: 323-350. PMID: 9143691, DOI: 10.1146/annurev.immunol.15.1.323.ChaptersConceptsExpression of NOS2Nitric oxide synthaseAdaptive immune systemNormal host cellsRemarkable molecular machinesInflammatory diseasesLymphocyte proliferationNO pathwayOxide synthaseImmune responseMacrophage productsMacrophage functionSuppressive effectImmune systemNOS2Nitric oxideHigh-output isoformTumor cellsMacrophagesCytotoxic actionElevated Ca2Transcriptional inductionFunctional dimerCytotoxic activityMolecular machinesAltered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase
MacMicking J, Nathan C, Hom G, Chartrain N, Fletcher D, Trumbauer M, Stevens K, Xie Q, Sokol K, Hutchinson N, Chen H, Mudget J. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995, 81: 641-650. PMID: 7538909, DOI: 10.1016/0092-8674(95)90085-3.Peer-Reviewed Original ResearchConceptsInducible nitric oxide synthaseINOS-/- miceNitric oxide synthaseOxide synthaseAnesthetized wild-type miceCentral arterial blood pressureArterial blood pressureWild-type miceBacterial endotoxic lipopolysaccharidesBlood pressureLiver damagePropionobacterium acnesEarly deathInfectious agentsTissue damageBacterial infectionsTumor cellsLymphoma cellsLipopolysaccharideAltered responseMiceEndotoxic lipopolysaccharideDeathListeria monocytogenesHypotensionInhibition of Viral Replication by Interferon-γ-Induced Nitric Oxide Synthase
Karupiah G, Xie Q, Buller R, Nathan C, Duarte C, MacMicking J. Inhibition of Viral Replication by Interferon-γ-Induced Nitric Oxide Synthase. Science 1993, 261: 1445-1448. PMID: 7690156, DOI: 10.1126/science.7690156.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid OxidoreductasesAnimalsArginineCell LineCells, CulturedEctromelia virusEctromelia, InfectiousEnzyme InductionFemaleHumansInterferon-gammaMacrophagesMiceMice, Inbred C57BLNitric OxideNitric Oxide SynthaseOmega-N-MethylarginineSimplexvirusTransfectionVaccinia virusVirus ReplicationConceptsViral replicationIFN-gammaHerpes simplex-1 virusNitric oxideDetectable NO synthesisSubstantial antiviral effectEctromelia virus infectionNitric oxide synthaseInducible NO synthaseIFN-gamma-treated macrophagesOxide synthaseAntiviral effectVirus infectionNO synthaseNO synthesisAntiviral activityInterferonEpithelial cellsMouse macrophagesCell productionMacrophagesCell typesSynthaseInhibitors
2019
Cell-autonomous immunity by IFN-induced GBPs in animals and plants
Huang S, Meng Q, Maminska A, MacMicking JD. Cell-autonomous immunity by IFN-induced GBPs in animals and plants. Current Opinion In Immunology 2019, 60: 71-80. PMID: 31176142, PMCID: PMC6800610, DOI: 10.1016/j.coi.2019.04.017.Peer-Reviewed Original ResearchConceptsGuanylate binding proteinsHost cell interiorCell-autonomous immunitySensory hubMammalian cytosolAnimal kingdomDownstream effectorsDirect bactericidal activityHost cellsBinding proteinCell interiorBacterial pathogensPlantsRecruitment platformDefensive repertoireArabidopsisOrthologuesGTPasesPhytopathogensBacterial colonizationMicrobesCytosolEffectorsProteinColonization
2009
Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P2 and PtdIns(3,4,5)P3 promotes immunity to mycobacteria
Tiwari S, Choi HP, Matsuzawa T, Pypaert M, MacMicking JD. Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P2 and PtdIns(3,4,5)P3 promotes immunity to mycobacteria. Nature Immunology 2009, 10: 907-917. PMID: 19620982, PMCID: PMC2715447, DOI: 10.1038/ni.1759.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedGTP-Binding ProteinsImmunity, InnateInterferon-gammaIntracellular MembranesLysosomesMacrophagesMiceMycobacterium tuberculosisPhagosomesPhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesProtein BindingProtein Structure, SecondaryProtein TransportSignal TransductionSNARE Proteins
1999
Phenotype of Mice and Macrophages Deficient in Both Phagocyte Oxidase and Inducible Nitric Oxide Synthase
Shiloh M, MacMicking J, Nicholson S, Brause J, Potter S, Marino M, Fang F, Dinauer M, Nathan C. Phenotype of Mice and Macrophages Deficient in Both Phagocyte Oxidase and Inducible Nitric Oxide Synthase. Immunity 1999, 10: 29-38. PMID: 10023768, DOI: 10.1016/s1074-7613(00)80004-7.Peer-Reviewed Original ResearchMeSH KeywordsAbscessAnimalsBacterial InfectionsCrosses, GeneticEscherichia coliGenetic Predisposition to DiseaseListeria monocytogenesListeriosisMacrophages, PeritonealMembrane GlycoproteinsMiceMice, Inbred C57BLMice, Inbred StrainsMice, KnockoutNADPH Oxidase 2NADPH OxidasesNitric Oxide SynthaseNitric Oxide Synthase Type IIPhenotypeSalmonella Infections, AnimalSalmonella typhimuriumConceptsInducible nitric oxide synthaseNitric oxide synthaseOxide synthaseSpecific pathogen-free conditionsPathogen-free conditionsPhagocyte oxidaseMassive abscessReactive oxygen intermediatesSuch infectionsPhenotype of miceCommensal organismsNitrogen intermediatesMiceOxygen intermediatesNOS2MacrophagesS. typhimuriumVirulent ListeriaEnteric bacteria
1998
Identification of Nitric Oxide Synthase 2 as an Innate Resistance Locus against Ectromelia Virus Infection
Karupiah G, Chen J, Nathan C, Mahalingam S, MacMicking J. Identification of Nitric Oxide Synthase 2 as an Innate Resistance Locus against Ectromelia Virus Infection. Journal Of Virology 1998, 72: 7703-7706. PMID: 9696880, PMCID: PMC110049, DOI: 10.1128/jvi.72.9.7703-7706.1998.Peer-Reviewed Original ResearchConceptsNitric oxide synthase 2NOS2-/- miceEctromelia virusCytotoxic T lymphocyte activityEctromelia virus infectionGamma interferon secretionT lymphocyte activityAcute viral infectionSynthase 2Lymphocyte activityNK cellsInterferon secretionVirus infectionImmune responseMonogenic determinantsViral infectionHost survivalCausative agentInfectionMousepoxSecretion