2024
Beyond antiviral: role of IFN-I in brain development
Baker C, Iwasaki A. Beyond antiviral: role of IFN-I in brain development. Trends In Immunology 2024, 45: 322-324. PMID: 38644134, DOI: 10.1016/j.it.2024.04.004.Commentaries, Editorials and LettersMeSH KeywordsAnimalsBrainHumansInterferon Type IMiceMicrogliaNeuronal PlasticityNeuronsPhagocytosisSignal Transduction
2023
IL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory
Micevic G, Daniels A, Flem-Karlsen K, Park K, Talty R, McGeary M, Mirza H, Blackburn H, Sefik E, Cheung J, Hornick N, Aizenbud L, Joshi N, Kluger H, Iwasaki A, Bosenberg M, Flavell R. IL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2304319120. PMID: 37459511, PMCID: PMC10372654, DOI: 10.1073/pnas.2304319120.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigensCD8-Positive T-LymphocytesHumansImmunologic MemoryLicensureMelanomaMemory T CellsMiceSignal TransductionConceptsIL-7R expressionT cellsIL-7RAntitumor memorySuperior antitumor efficacyCell-based therapiesTumor-specific T cellsAntigen-specific T cellsAntitumor efficacyPowerful antitumor immune responseMarkers of exhaustionTumor-specific CD8Antitumor immune responseIndependent prognostic factorAntitumor immune memoryMemory T cellsMajor risk factorSuperior antitumor activityFunctional CD8Memory CD8Prognostic factorsSurgical resectionAdvanced melanomaLymph nodesNaive miceType 2 Dendritic Cells Orchestrate a Local Immune Circuit to Confer Antimetastatic Immunity
Weizman O, Luyten S, Krykbaeva I, Song E, Mao T, Bosenberg M, Iwasaki A. Type 2 Dendritic Cells Orchestrate a Local Immune Circuit to Confer Antimetastatic Immunity. The Journal Of Immunology 2023, 210: 1146-1155. PMID: 36881866, PMCID: PMC10067787, DOI: 10.4049/jimmunol.2200697.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCytokinesDendritic CellsImmunity, InnateKiller Cells, NaturalMiceSignal TransductionConceptsType 2 dendritic cellsMetastatic burdenImmune circuitsDendritic cellsConventional type 2 dendritic cellsSyngeneic murine melanomaNK cell compartmentImmune cell responsesColon cancer modelEarly metastatic seedingMetastatic controlTranscription factor IRF3DC populationsNK cellsProinflammatory cytokinesNucleic acid sensingPrimary tumorEffector responsesMetastatic spreadDisease outcomeIntracardiac injectionT cellsInitial immunityTissue-specific ablationCancer model
2021
Kynurenic acid may underlie sex-specific immune responses to COVID-19
Cai Y, Kim DJ, Takahashi T, Broadhurst DI, Yan H, Ma S, Rattray NJW, Casanovas-Massana A, Israelow B, Klein J, Lucas C, Mao T, Moore AJ, Muenker MC, Oh JE, Silva J, Wong P, team Y, Ko AI, Khan SA, Iwasaki A, Johnson CH. Kynurenic acid may underlie sex-specific immune responses to COVID-19. Science Signaling 2021, 14: eabf8483. PMID: 34230210, PMCID: PMC8432948, DOI: 10.1126/scisignal.abf8483.Peer-Reviewed Original ResearchConceptsKynurenic acidImmune responseClinical outcomesSex-specific immune responsesT cell responsesPoor clinical outcomeCOVID-19 patientsCoronavirus disease 2019COVID-19Sex-related differencesMale patientsCytokine abundanceInflammatory cytokinesKynurenine ratioSerum metabolomeDisease 2019Sex-specific linkKynurenine aminotransferaseCell responsesOld malePatientsMalesOutcomesResponseMetabolites
2020
Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling
Israelow B, Song E, Mao T, Lu P, Meir A, Liu F, Alfajaro MM, Wei J, Dong H, Homer RJ, Ring A, Wilen CB, Iwasaki A. Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling. Journal Of Experimental Medicine 2020, 217: e20201241. PMID: 32750141, PMCID: PMC7401025, DOI: 10.1084/jem.20201241.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2AnimalsBetacoronavirusCell Line, TumorCoronavirus InfectionsCOVID-19DependovirusDisease Models, AnimalFemaleHumansInflammationInterferon Type ILungMaleMiceMice, Inbred C57BLMice, TransgenicPandemicsParvoviridae InfectionsPeptidyl-Dipeptidase APneumonia, ViralSARS-CoV-2Signal TransductionVirus ReplicationConceptsSARS-CoV-2Type I interferonMouse modelI interferonRobust SARS-CoV-2 infectionSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2SARS-CoV-2 infectionRespiratory syndrome coronavirus 2SARS-CoV-2 replicationCOVID-19 patientsSyndrome coronavirus 2Patient-derived virusesSignificant fatality ratePathological findingsInflammatory rolePathological responseEnzyme 2Receptor angiotensinFatality rateVaccine developmentGenetic backgroundViral replicationCoronavirus diseaseMiceInflammasomes and Pyroptosis as Therapeutic Targets for COVID-19
Yap JKY, Moriyama M, Iwasaki A. Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19. The Journal Of Immunology 2020, 205: ji2000513. PMID: 32493814, PMCID: PMC7343621, DOI: 10.4049/jimmunol.2000513.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsAntiviral AgentsBetacoronavirusCoronavirus InfectionsCOVID-19COVID-19 Drug TreatmentHumansImmunity, InnateInflammasomesIntercellular Signaling Peptides and ProteinsMacrophages, AlveolarPandemicsPneumonia, ViralPyroptosisSARS-CoV-2Severe acute respiratory syndrome-related coronavirusSignal TransductionConceptsSevere acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infectionSevere acute respiratory syndrome-related coronavirus 2Coronavirus disease 2019 (COVID-19) patientsSevere coronavirus disease 2019Coronavirus 2 infectionAvailable pharmaceutical agentsCoronavirus disease 2019Innate immune pathwaysClinical outcomesCoronavirus 2Inflammatory responseCellular pyroptosisDisease 2019Downstream cytokinesInflammasome activationInflammasome pathwayTherapeutic targetImmune pathwaysPromising targetPharmaceutical agentsCOVID-19PyroptosisPatientsCytokinesInflammasomeType I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19
Park A, Iwasaki A. Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host & Microbe 2020, 27: 870-878. PMID: 32464097, PMCID: PMC7255347, DOI: 10.1016/j.chom.2020.05.008.Peer-Reviewed Original ResearchConceptsSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Syndrome coronavirus 2Role of interferonType ICoronavirus disease 2019COVID-19Innate antiviral responseOngoing global threatCoronavirus 2Pathogenic coronavirusesTreatment strategiesDisease 2019Protective effectHuman coronavirusesRecombinant interferonMERS-CoVSARS-CoVAntiviral responseInterferonAntiviral therapeuticsCombat COVID-19Interferon inductionGlobal pandemicCutting Edge: The Use of Topical Aminoglycosides as an Effective Pull in "Prime and Pull" Vaccine Strategy.
Gopinath S, Lu P, Iwasaki A. Cutting Edge: The Use of Topical Aminoglycosides as an Effective Pull in "Prime and Pull" Vaccine Strategy. The Journal Of Immunology 2020, 204: 1703-1707. PMID: 32122994, DOI: 10.4049/jimmunol.1900462.Peer-Reviewed Original ResearchConceptsTissue-resident memory T cellsGenital herpes infectionMemory T cellsT cellsHerpes infectionVirus-specific effector T cellsVaginal applicationTopical vaginal applicationCD8 T cellsEffector T cellsProtective immune responseSingle topical applicationTopical aminoglycosidesGenital mucosaChemokine expressionVaccine strategiesImmune responseVaginal mucosaTopical applicationBarrier tissuesMiceRobust activationAminoglycoside antibioticsMucosaInfection
2019
RIG-I Recognition of RNA Targets: The Influence of Terminal Base Pair Sequence and Overhangs on Affinity and Signaling
Ren X, Linehan MM, Iwasaki A, Pyle AM. RIG-I Recognition of RNA Targets: The Influence of Terminal Base Pair Sequence and Overhangs on Affinity and Signaling. Cell Reports 2019, 29: 3807-3815.e3. PMID: 31851914, DOI: 10.1016/j.celrep.2019.11.052.Peer-Reviewed Original ResearchConceptsRNA moleculesRIG-I activationBase pair sequenceHost RNA moleculesViral RNA moleculesRIG-I recognitionMolecular basisRNA variantsRNA targetsPair sequenceHuman cellsBase pairsImmune receptorsMechanisms of evasionTerminal base pairsLigand affinityWhole animalInterferon responseDeadly pathogenRNA therapeuticsMarburg virusCellsOverhangMoleculesSignalingMurine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice
Pi R, Iwasaki A, Sewald X, Mothes W, Uchil PD. Murine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice. Journal Of Virology 2019, 93: 10.1128/jvi.00930-19. PMID: 31434732, PMCID: PMC6803250, DOI: 10.1128/jvi.00930-19.Peer-Reviewed Original ResearchConceptsPopliteal lymph nodesFriend murine leukemia virusInnate immune sensing pathwaysToll-like receptor 7Viral spreadMurine leukemia virusCell-deficient miceType I interferon responseWild-type miceCell populationsType I interferonLeukemia virusRobust virus replicationI interferon responseAntiviral intervention strategiesInfected cell typesSentinel macrophagesAdoptive transferCell typesLymph nodesReceptor 7Virus infectionInnate sensingB cellsI interferon
2018
An Antiviral Branch of the IL-1 Signaling Pathway Restricts Immune-Evasive Virus Replication
Orzalli MH, Smith A, Jurado KA, Iwasaki A, Garlick JA, Kagan JC. An Antiviral Branch of the IL-1 Signaling Pathway Restricts Immune-Evasive Virus Replication. Molecular Cell 2018, 71: 825-840.e6. PMID: 30100266, PMCID: PMC6411291, DOI: 10.1016/j.molcel.2018.07.009.Peer-Reviewed Original ResearchConceptsDamage-associated molecular patternsIL-1Host-derived damage-associated molecular patternsViral replicationVirus replicationInfected cellsInterleukin-1 family cytokinesIL-1 Signaling PathwayInflammatory gene expressionIL-1 actsHuman skin explantsProtective immunityIL-1αBarrier defenseInflammatory signalsViral infectionFamily cytokinesSkin explantsGene expressionMolecular patternsSkin fibroblastsSignaling pathwaysAntiviral systemBarrier epitheliaCell typesKDM5 histone demethylases repress immune response via suppression of STING
Wu L, Cao J, Cai WL, Lang SM, Horton JR, Jansen DJ, Liu ZZ, Chen JF, Zhang M, Mott BT, Pohida K, Rai G, Kales SC, Henderson MJ, Hu X, Jadhav A, Maloney DJ, Simeonov A, Zhu S, Iwasaki A, Hall MD, Cheng X, Shadel GS, Yan Q. KDM5 histone demethylases repress immune response via suppression of STING. PLOS Biology 2018, 16: e2006134. PMID: 30080846, PMCID: PMC6095604, DOI: 10.1371/journal.pbio.2006134.Peer-Reviewed Original ResearchConceptsImmune responseSTING expressionCyclic GMP-AMP synthase stimulatorSuppression of STINGCancer cellsCancer immunotherapy agentsHuman papilloma virusAdaptive immune responsesMultiple clinical trialsExpression of STINGBreast cancer cellsInnate immune defenseRobust interferon responseMultiple cancer typesIntratumoral CD8Immunotherapy agentsAnticancer immunotherapyPatient survivalNeck cancerPapilloma virusClinical trialsT cellsSTING agonistsKDM5 histonePositive head
2017
Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes
Molony RD, Nguyen JT, Kong Y, Montgomery RR, Shaw AC, Iwasaki A. Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes. Science Signaling 2017, 10 PMID: 29233916, PMCID: PMC6429941, DOI: 10.1126/scisignal.aan2392.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAgingDEAD Box Protein 58FemaleHumansImmunity, InnateInterferonsMaleMonocytesReceptors, ImmunologicSignal TransductionConceptsType I IFNsI IFNsI interferonOlder adultsIFN inductionRetinoic acid-inducible gene IAcid-inducible gene IHealthy human donorsType I interferonRespiratory influenzaProinflammatory cytokinesVirus infectionType I IFN genesAdult monocytesAntiviral resistanceTranscription factor IRF8IFN responseHuman donorsMonocytesIncreased proteasomal degradationHuman monocytesYoung adultsIRF8 expressionIAV RNAInfected cellsType I IFN Is Necessary and Sufficient for Inflammation-Induced Red Blood Cell Alloimmunization in Mice
Gibb DR, Liu J, Natarajan P, Santhanakrishnan M, Madrid DJ, Eisenbarth SC, Zimring JC, Iwasaki A, Hendrickson JE. Type I IFN Is Necessary and Sufficient for Inflammation-Induced Red Blood Cell Alloimmunization in Mice. The Journal Of Immunology 2017, 199: 1041-1050. PMID: 28630094, PMCID: PMC5568771, DOI: 10.4049/jimmunol.1700401.Peer-Reviewed Original ResearchConceptsRBC alloimmunizationRed blood cell alloimmunizationCertain inflammatory disordersCompatible blood productsProduction of alloantibodiesHemolytic transfusion reactionsCytosolic pattern recognition receptorsType I IFNsTransgenic murine modelType I IFNPattern recognition receptorsTransfusion protocolAlloimmune responseRBC transfusionInflammatory disordersInflammatory conditionsTransfusion reactionsBlood productsInflammatory stimuliMurine modelI IFNsAlloimmunizationI IFNViral infectionRecognition receptors
2015
Tissue instruction for migration and retention of TRM cells
Iijima N, Iwasaki A. Tissue instruction for migration and retention of TRM cells. Trends In Immunology 2015, 36: 556-564. PMID: 26282885, PMCID: PMC4567393, DOI: 10.1016/j.it.2015.07.002.Peer-Reviewed Original ResearchConceptsTissue-resident memory T cellsMemory lymphocyte clustersTRM cellsT cellsCD4 tissue-resident memory T cellsRobust local immune responseCD8 TRM cellsEffector T cellsLocal immune responseMemory T cellsNon-lymphoid tissuesLymphocyte clustersImmune responseInfectious agentsIncoming pathogensCell homingRecent findingsCellsInfectionFindingsToll-like receptor 9 trafficking and signaling for type I interferons requires PIKfyve activity
Hayashi K, Sasai M, Iwasaki A. Toll-like receptor 9 trafficking and signaling for type I interferons requires PIKfyve activity. International Immunology 2015, 27: 435-445. PMID: 25925170, PMCID: PMC4560039, DOI: 10.1093/intimm/dxv021.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineCell MembraneDendritic CellsDNA-Binding ProteinsEndosomesInterferon Type ILysosome-Associated Membrane GlycoproteinsMiceMice, Inbred C57BLPhosphatidylinositol 3-KinasesProtein TransportSignal TransductionToll-Like Receptor 7Toll-Like Receptor 9Transcription FactorsVesicle-Associated Membrane Protein 3ConceptsDifferent dendritic cell subsetsIFN inductionDendritic cell subsetsInduction of cytokinesType I IFN inductionType I IFNType I interferonI IFN inductionViral nucleic acidsAnti-viral programsTLR9 traffickingCell subsetsTLR9 signalsI IFNI interferonInhibitor treatmentDistinct subcellular membranesRAW264.7 cellsType I interferon (IFN) genesTLR9Distinct endosomal compartmentsInterferon genesTLR traffickingConfocal microscopyInduction
2014
Apoptotic Caspases Prevent the Induction of Type I Interferons by Mitochondrial DNA
Rongvaux A, Jackson R, Harman CC, Li T, West AP, de Zoete MR, Wu Y, Yordy B, Lakhani SA, Kuan CY, Taniguchi T, Shadel GS, Chen ZJ, Iwasaki A, Flavell RA. Apoptotic Caspases Prevent the Induction of Type I Interferons by Mitochondrial DNA. Cell 2014, 159: 1563-1577. PMID: 25525875, PMCID: PMC4272443, DOI: 10.1016/j.cell.2014.11.037.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCaspasesDNA, MitochondrialInflammationInterferon Type IMiceMice, KnockoutSignal TransductionVirus DiseasesConceptsMitochondrial outer membrane permeabilizationCell deathOuter membrane permeabilizationType I interferonDNA-dependent activationCaspase-dependent mannerI interferonCGAS/STING pathwayMitochondrial DNAApoptotic caspasesMembrane permeabilizationActive caspasesProapoptotic caspasesMitochondriaCaspasesSTING pathwayIFN responseAntiviral immunityCentral roleDual controlPathwayProinflammatory typeInductionCellsActivationAlternative Capture of Noncoding RNAs or Protein-Coding Genes by Herpesviruses to Alter Host T Cell Function
Guo YE, Riley KJ, Iwasaki A, Steitz JA. Alternative Capture of Noncoding RNAs or Protein-Coding Genes by Herpesviruses to Alter Host T Cell Function. Molecular Cell 2014, 54: 67-79. PMID: 24725595, PMCID: PMC4039351, DOI: 10.1016/j.molcel.2014.03.025.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDAntigens, Differentiation, T-LymphocyteBase SequenceCallithrixEnzyme ActivationGene Expression RegulationGPI-Linked ProteinsGRB2 Adaptor ProteinHEK293 CellsHerpesvirus 2, SaimiriineHigh-Throughput Nucleotide SequencingHost-Pathogen InteractionsHumansImmunoprecipitationInterferon-gammaJurkat CellsLectins, C-TypeLymphocyte ActivationMicroRNAsMitogen-Activated Protein KinasesMolecular Sequence DataReceptors, Antigen, T-CellRNA StabilityRNA, UntranslatedRNA, ViralSemaphorinsSequence Analysis, RNASignal TransductionTime FactorsT-LymphocytesTransfectionConceptsMitogen-activated protein kinaseMiR-27Protein coding genesHerpesvirus saimiriHigh-throughput sequencingTCR-induced activationCell functionHSUR 1Γ-herpesvirusesNoncoding RNAsProtein kinaseEctopic expressionOncogenic γ-herpesvirusesTarget genesInduction of CD69MicroRNA-27Key modulatorRNACommon targetAlHV-1GenesCell receptorDiverse strategiesHost T-cell functionCellsA Promiscuous Lipid-Binding Protein Diversifies the Subcellular Sites of Toll-like Receptor Signal Transduction
Bonham KS, Orzalli MH, Hayashi K, Wolf AI, Glanemann C, Weninger W, Iwasaki A, Knipe DM, Kagan JC. A Promiscuous Lipid-Binding Protein Diversifies the Subcellular Sites of Toll-like Receptor Signal Transduction. Cell 2014, 156: 705-716. PMID: 24529375, PMCID: PMC3951743, DOI: 10.1016/j.cell.2014.01.019.Peer-Reviewed Original ResearchConceptsToll-like receptorsToll-like receptor signal transductionSignal transductionDifferent organellesProinflammatory cytokine expressionSubcellular sitesInnate immune signal transductionInnate immune systemPhosphoinositide-binding domainsImmune signal transductionLipid binding proteinMultiple subcellular locationsReceptor signal transductionCytokine expressionLipid targetsImmune systemInnate immunityHost defenseProtein complexesSubcellular locationPlasma membraneAdaptor TIRAPTIRAPNatural activatorFamily membersEpigenetic Reprogramming of the Type III Interferon Response Potentiates Antiviral Activity and Suppresses Tumor Growth
Ding S, Khoury-Hanold W, Iwasaki A, Robek MD. Epigenetic Reprogramming of the Type III Interferon Response Potentiates Antiviral Activity and Suppresses Tumor Growth. PLOS Biology 2014, 12: e1001758. PMID: 24409098, PMCID: PMC3883642, DOI: 10.1371/journal.pbio.1001758.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell Line, TumorCell ProliferationCpG IslandsCricetinaeCytomegalovirusDNA MethylationEpigenesis, GeneticHepatocytesHerpesvirus 1, HumanHistone Deacetylase InhibitorsHistone DeacetylasesHost-Pathogen InteractionsHumansInterferon-gammaMiceNIH 3T3 CellsOrgan SpecificityPromoter Regions, GeneticReceptors, CytokineReceptors, InterferonRNA, Small InterferingSignal TransductionVesiculovirusConceptsHDAC inhibitorsPro-apoptotic activityRepression machineryExpression programsTranscriptional silencingEpigenetic reprogrammingEpigenetic rewiringUbiquitous expressionMolecular mechanismsCell typesSpecific mannerSuppress tumor growthReceptor subunitsPotential antitumor strategyNonresponsive cellsIFN responseAntiviral immunityViral pathogensExpressionReceptor expressionType III interferonsAntitumor strategyΒ receptorTumor growthEpithelial origin