2022
Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19
Unterman A, Sumida TS, Nouri N, Yan X, Zhao AY, Gasque V, Schupp JC, Asashima H, Liu Y, Cosme C, Deng W, Chen M, Raredon MSB, Hoehn KB, Wang G, Wang Z, DeIuliis G, Ravindra NG, Li N, Castaldi C, Wong P, Fournier J, Bermejo S, Sharma L, Casanovas-Massana A, Vogels CBF, Wyllie AL, Grubaugh ND, Melillo A, Meng H, Stein Y, Minasyan M, Mohanty S, Ruff WE, Cohen I, Raddassi K, Niklason L, Ko A, Montgomery R, Farhadian S, Iwasaki A, Shaw A, van Dijk D, Zhao H, Kleinstein S, Hafler D, Kaminski N, Dela Cruz C. Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19. Nature Communications 2022, 13: 440. PMID: 35064122, PMCID: PMC8782894, DOI: 10.1038/s41467-021-27716-4.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAgedAntibodies, Monoclonal, HumanizedCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCells, CulturedCOVID-19COVID-19 Drug TreatmentFemaleGene Expression ProfilingGene Expression RegulationHumansImmunity, InnateMaleReceptors, Antigen, B-CellReceptors, Antigen, T-CellRNA-SeqSARS-CoV-2Single-Cell AnalysisConceptsProgressive COVID-19B cell clonesSingle-cell analysisT cellsImmune responseMulti-omics single-cell analysisCOVID-19Cell clonesAdaptive immune interactionsSevere COVID-19Dynamic immune responsesGene expressionSARS-CoV-2 virusAdaptive immune systemSomatic hypermutation frequenciesCellular effectsProtein markersEffector CD8Immune signaturesProgressive diseaseHypermutation frequencyProgressive courseClassical monocytesClonesImmune interactions
2021
Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes
Ravindra NG, Alfajaro MM, Gasque V, Huston NC, Wan H, Szigeti-Buck K, Yasumoto Y, Greaney AM, Habet V, Chow RD, Chen JS, Wei J, Filler RB, Wang B, Wang G, Niklason LE, Montgomery RR, Eisenbarth SC, Chen S, Williams A, Iwasaki A, Horvath TL, Foxman EF, Pierce RW, Pyle AM, van Dijk D, Wilen CB. Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes. PLOS Biology 2021, 19: e3001143. PMID: 33730024, PMCID: PMC8007021, DOI: 10.1371/journal.pbio.3001143.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionSARS-CoV-2Human bronchial epithelial cellsInterferon-stimulated genesCell state changesAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSyndrome coronavirus 2 infectionCell tropismCoronavirus 2 infectionCoronavirus disease 2019Onset of infectionCell-intrinsic expressionCourse of infectionAir-liquid interface culturesHost-viral interactionsBronchial epithelial cellsSingle-cell RNA sequencingCell typesIL-1Disease 2019Human airwaysDevelopment of therapeuticsDrug AdministrationViral replication
2018
Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus
Mihaylova VT, Kong Y, Fedorova O, Sharma L, Dela Cruz CS, Pyle AM, Iwasaki A, Foxman EF. Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus. Cell Reports 2018, 24: 3000-3007.e3. PMID: 30208323, PMCID: PMC6190718, DOI: 10.1016/j.celrep.2018.08.033.Peer-Reviewed Original ResearchConceptsRIG-I stimulationAntiviral responseRhinovirus infectionBronchial airway epithelial cellsAcute respiratory infectionsEpithelial cellsRobust antiviral responseAirway epithelial cellsPrimary human nasalAirway damageRespiratory infectionsAirway microenvironmentAsthma attacksNasal mucosaLeading causeNrf2 knockdownNasal cellsNrf2 activationHuman nasalEpithelial defenseHost defenseBronchial cellsInfectionOxidative stressRhinovirus
2017
IRE1α promotes viral infection by conferring resistance to apoptosis
Fink SL, Jayewickreme TR, Molony RD, Iwawaki T, Landis CS, Lindenbach BD, Iwasaki A. IRE1α promotes viral infection by conferring resistance to apoptosis. Science Signaling 2017, 10 PMID: 28588082, PMCID: PMC5535312, DOI: 10.1126/scisignal.aai7814.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCase-Control StudiesCells, CulturedEndoribonucleasesFemaleHepacivirusHepatitis CHerpes SimplexHumansLiverMaleMiceMice, KnockoutMicroRNAsProtein Serine-Threonine KinasesSimplexvirusVesicular StomatitisVesicular stomatitis Indiana virusViral Nonstructural ProteinsVirus ReplicationX-Box Binding Protein 1ConceptsX-box binding protein 1Type I IFN responseI IFN responseUnfolded protein responseViral-induced apoptosisActivation of IRE1αLiver biopsyAntiviral therapyHealthy controlsAntiviral resistanceViral infectionBinding protein 1Antiapoptotic Bcl-2 familyIFN responseViral replicationDeficient cellsProtein 1Apoptosis resistancePossible targetsProsurvival roleEnzyme 1αApoptosisInfectionIntrinsic pathwayType I
2016
Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature
Foxman EF, Storer JA, Vanaja K, Levchenko A, Iwasaki A. Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: 8496-8501. PMID: 27402752, PMCID: PMC4968739, DOI: 10.1073/pnas.1601942113.Peer-Reviewed Original ResearchConceptsIFN-independent mechanismsEpithelial cellsHost defense strategiesHost cell deathIFN inductionHuman bronchial epithelial cellsReduced virus productionCommon cold virusInfected epithelial cellsB-cell lymphoma 2 (Bcl-2) overexpressionBronchial epithelial cellsDiverse stimuliViral replicationAntiviral pathwaysCell deathH1-HeLa cellsTemperature-dependent replicationCell typesSingle replication cycleTemperature-dependent growthReplication cycleWarmer temperaturesCool temperaturesDefense strategiesType 1 IFN responseAXL receptor tyrosine kinase is required for T cell priming and antiviral immunity
Schmid ET, Pang IK, Silva E, Bosurgi L, Miner JJ, Diamond MS, Iwasaki A, Rothlin CV. AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity. ELife 2016, 5: e12414. PMID: 27350258, PMCID: PMC4924996, DOI: 10.7554/elife.12414.Peer-Reviewed Original ResearchConceptsType I IFNsI IFNsI interferonDendritic cellsIL-1βAntiviral T cell immunityAntiviral adaptive immunityPotent immunosuppressive functionT cell immunityT cell primingInhibition of AXLType I IFN receptorAxl receptor tyrosine kinaseReceptor tyrosine kinase AXLControl of infectionType I interferonI IFN receptorTyrosine kinase AXLDC maturationCell immunityWest Nile virusCell primingImmunosuppressive functionImmunosuppressive effectsAdaptive immunity
2013
ELF4 is critical for induction of type I interferon and the host antiviral response
You F, Wang P, Yang L, Yang G, Zhao YO, Qian F, Walker W, Sutton R, Montgomery R, Lin R, Iwasaki A, Fikrig E. ELF4 is critical for induction of type I interferon and the host antiviral response. Nature Immunology 2013, 14: 1237-1246. PMID: 24185615, PMCID: PMC3939855, DOI: 10.1038/ni.2756.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineCells, CulturedDNA-Binding ProteinsHEK293 CellsHeLa CellsHost-Pathogen InteractionsHumansImmunoblottingInterferon Regulatory Factor-3Interferon Regulatory Factor-7Interferon-betaMembrane ProteinsMiceMice, Inbred C57BLMice, KnockoutMicroscopy, ConfocalProtein BindingReverse Transcriptase Polymerase Chain ReactionRNA InterferenceSignal TransductionSurvival AnalysisTranscription FactorsTranscriptional ActivationWest Nile FeverWest Nile virusHigh-risk human papillomavirus E6 inhibits monocyte differentiation to Langerhans cells
Iijima N, Goodwin EC, DiMaio D, Iwasaki A. High-risk human papillomavirus E6 inhibits monocyte differentiation to Langerhans cells. Virology 2013, 444: 257-262. PMID: 23871219, PMCID: PMC3755085, DOI: 10.1016/j.virol.2013.06.020.Peer-Reviewed Original ResearchConceptsHigh-risk human papillomavirusLangerhans cellsHigh-risk HPVCompetent antigen presenting cellsHPV-positive cancer cellsKey antigen-presenting cellsHPV-positive cervical cancer cellsCancer cellsHuman peripheral blood monocytesAntigen-presenting cellsAntigen presenting cellsImmune evasion strategiesPeripheral blood monocytesVariety of malignanciesCervical cancer cellsContact-dependent mannerDifferentiation of monocytesHuman papillomavirusPresenting cellsImmune surveillanceSquamous epitheliumBlood monocytesMucosal epitheliumHPV E6HPV16 E6Toll-Like Receptor 9 in Plasmacytoid Dendritic Cells Fails To Detect Parvoviruses
Mattei LM, Cotmore SF, Li L, Tattersall P, Iwasaki A. Toll-Like Receptor 9 in Plasmacytoid Dendritic Cells Fails To Detect Parvoviruses. Journal Of Virology 2013, 87: 3605-3608. PMID: 23302877, PMCID: PMC3592163, DOI: 10.1128/jvi.03155-12.Peer-Reviewed Original Research
2012
Adaptor Protein-3 in Dendritic Cells Facilitates Phagosomal Toll-like Receptor Signaling and Antigen Presentation to CD4+ T Cells
Mantegazza AR, Guttentag SH, El-Benna J, Sasai M, Iwasaki A, Shen H, Laufer TM, Marks MS. Adaptor Protein-3 in Dendritic Cells Facilitates Phagosomal Toll-like Receptor Signaling and Antigen Presentation to CD4+ T Cells. Immunity 2012, 36: 782-794. PMID: 22560444, PMCID: PMC3361531, DOI: 10.1016/j.immuni.2012.02.018.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Protein Complex 3AnimalsAntigen PresentationAntigensCD4-Positive T-LymphocytesCell DifferentiationCell MembraneCells, CulturedDendritic CellsEndocytosisHistocompatibility Antigens Class IILigandsListeria monocytogenesListeriosisMiceMice, Inbred C57BLMice, TransgenicMyeloid Differentiation Factor 88OvalbuminPeptidesPhagocytosisPhagosomesSignal TransductionTh1 CellsToll-Like ReceptorsConceptsToll-like receptor signalingDendritic cellsAntigen presentationAdaptor protein 3Protein 3Receptor signalingMHC-II presentationEffector cell functionListeria monocytogenes infectionTLR ligandsMonocytogenes infectionTLR4 recruitmentT cellsCell activationIntracellular storesPhagolysosome maturationCell functionPearl miceReceptor-mediated endocytosisAntigenPresentationMolecular mechanismsPhagosomesCell surfaceSignaling
2010
Bifurcation of Toll-Like Receptor 9 Signaling by Adaptor Protein 3
Sasai M, Linehan MM, Iwasaki A. Bifurcation of Toll-Like Receptor 9 Signaling by Adaptor Protein 3. Science 2010, 329: 1530-1534. PMID: 20847273, PMCID: PMC3063333, DOI: 10.1126/science.1187029.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Protein Complex 3Adaptor Protein Complex beta SubunitsAnimalsCells, CulturedCytokinesCytoplasmic VesiclesDendritic CellsEndosomesInterferon Regulatory Factor-7Interferon Type ILysosomal-Associated Membrane Protein 2MacrophagesMembrane Transport ProteinsMiceMice, Inbred C57BLMyeloid Differentiation Factor 88OligodeoxyribonucleotidesProtein TransportRecombinant Fusion ProteinsSignal TransductionTNF Receptor-Associated Factor 3Toll-Like Receptor 9Transcriptional ActivationVesicle-Associated Membrane Protein 3ConceptsI interferonTLR9 signalsEndosomal Toll-like receptors 7Toll-like receptor 9 signalingToll-like receptor 7Protein 3Type I IFNsDependent proinflammatory cytokinesInterferon regulatory factor 7I IFNsProinflammatory cytokine genesType I interferonNuclear factor κBRegulatory factor 7Viral nucleic acidsProinflammatory cytokinesReceptor 7Factor κBCytokine genesTLR9Adaptor protein 3Intracellular mechanismsFactor 7Viral pathogensReceptor traffickingInfluenza virus activates inflammasomes via its intracellular M2 ion channel
Ichinohe T, Pang IK, Iwasaki A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nature Immunology 2010, 11: 404-410. PMID: 20383149, PMCID: PMC2857582, DOI: 10.1038/ni.1861.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsCells, CulturedCytokinesDendritic CellsGenetic EngineeringGolgi ApparatusHydrogen-Ion ConcentrationIon ChannelsMacrophagesMembrane GlycoproteinsMiceMice, Inbred C57BLMice, KnockoutMonensinNLR Family, Pyrin Domain-Containing 3 ProteinOncogene Proteins, ViralOrthomyxoviridaeOrthomyxoviridae InfectionsPotassium ChlorideProtein TransportProtonsSequence DeletionToll-Like Receptor 7Viral Matrix ProteinsVirus ReplicationIn Vivo Requirement for Atg5 in Antigen Presentation by Dendritic Cells
Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A, Mizushima N, Grinstein S, Iwasaki A. In Vivo Requirement for Atg5 in Antigen Presentation by Dendritic Cells. Immunity 2010, 32: 227-239. PMID: 20171125, PMCID: PMC2996467, DOI: 10.1016/j.immuni.2009.12.006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigen PresentationAutophagy-Related Protein 5Cells, CulturedDendritic CellsFemaleHerpes SimplexHerpesvirus 2, HumanHistocompatibility Antigens Class IILymphocyte ActivationMiceMice, Inbred C57BLMice, KnockoutMicrotubule-Associated ProteinsRadiation ChimeraRNA, Small InterferingConceptsMHC-II presentationMHC class IIDendritic cellsAntigen presentationClass IIHerpes simplex virus infectionToll-like receptor stimuliT cell primingSimplex virus infectionCell primingAbsence of ATG5Microbial antigensVirus infectionMHC ICytosolic antigensConditional deletionAntigenReceptor stimuliAutophagic machineryKey autophagy genesRapid diseasePresentationATG5Lysosome fusionAutophagy genes
2009
Cholera toxin inhibits IL-12 production and CD8α+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function
la Sala A, He J, Laricchia-Robbio L, Gorini S, Iwasaki A, Braun M, Yap GS, Sher A, Ozato K, Kelsall B. Cholera toxin inhibits IL-12 production and CD8α+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function. Journal Of Experimental Medicine 2009, 206: 1227-1235. PMID: 19487420, PMCID: PMC2715075, DOI: 10.1084/jem.20080912.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD8 AntigensCD8-Positive T-LymphocytesCell DifferentiationCells, CulturedCholera ToxinCyclic AMPDendritic CellsFemaleGTP-Binding Protein alpha Subunits, GsHumansInterferon Regulatory Factor-1Interferon Regulatory FactorsInterferon-gammaInterleukin-12Interleukin-12 Subunit p40MiceMice, Inbred BALB CSpleenToxoplasmosisConceptsIL-12 productionDendritic cellsPlasmacytoid DCsCholera toxinSerum IL-12 levelsIL-12 levelsPlasmacytoid dendritic cellsConventional dendritic cellsIL-12p40 promoterDendritic cell differentiationConventional DCsP40 gene expressionBone marrow cellsInterferon regulatory factor 8Regulatory factor 8Th1 responseDC differentiationIL-12p35Lymphoid organsToxoplasma gondiiMarrow cellsDibutyryl cAMPIRF8Factor 8Common mechanismAbsence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling
Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS, Iwasaki A. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 2770-2775. PMID: 19196953, PMCID: PMC2650341, DOI: 10.1073/pnas.0807694106.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutophagyAutophagy-Related Protein 5Cells, CulturedDEAD Box Protein 58DEAD-box RNA HelicasesDNA, MitochondrialEnzyme-Linked Immunosorbent AssayFlow CytometryInterferon Type IMacrophagesMiceMicrotubule-Associated ProteinsMitochondriaReactive Oxygen SpeciesReverse Transcriptase Polymerase Chain ReactionSignal TransductionConceptsReactive oxygen speciesDysfunctional mitochondriaInnate antiviral defenseAntiviral defenseKey antiviral cytokinesAbsence of autophagyMitochondrial reactive oxygen speciesHomeostatic regulationRole of autophagyTreatment of cellsIPS-1RLR signalingVesicular stomatitis virusAutophagy resultsRNA virusesWT cellsMitochondriaAutophagyType I IFNStomatitis virusRLRLike receptorsOxygen speciesNeurodegenerative diseasesInflammatory disorders
2003
CD11b+ Peyer’s Patch Dendritic Cells Secrete IL-6 and Induce IgA Secretion from Naive B Cells
Sato A, Hashiguchi M, Toda E, Iwasaki A, Hachimura S, Kaminogawa S. CD11b+ Peyer’s Patch Dendritic Cells Secrete IL-6 and Induce IgA Secretion from Naive B Cells. The Journal Of Immunology 2003, 171: 3684-3690. PMID: 14500666, DOI: 10.4049/jimmunol.171.7.3684.Peer-Reviewed Original ResearchConceptsPP dendritic cellsNaive B cellsDendritic cellsIL-6B cellsIgA secretionDC subsetsIgA productionPeyer's patch dendritic cellsSecrete IL-6Exogenous IL-6Cell coculture systemDC populationsLymphoid organsCytokine secretionAb productionT cellsHigh levelsSpleenSecretionCoculture systemCellsIgAUnique roleDistinct capacities
2000
Requirements for the Maintenance of Th1 Immunity In Vivo Following DNA Vaccination: A Potential Immunoregulatory Role for CD8+ T Cells
Gurunathan S, Stobie L, Prussin C, Sacks D, Glaichenhaus N, Iwasaki A, Fowell D, Locksley R, Chang J, Wu C, Seder R. Requirements for the Maintenance of Th1 Immunity In Vivo Following DNA Vaccination: A Potential Immunoregulatory Role for CD8+ T Cells. The Journal Of Immunology 2000, 165: 915-924. PMID: 10878366, DOI: 10.4049/jimmunol.165.2.915.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, ProtozoanCD4 Lymphocyte CountCD4-Positive T-LymphocytesCD8 AntigensCD8-Positive T-LymphocytesCell DivisionCells, CulturedDNA, ProtozoanGenes, T-Cell Receptor betaImmune SeraImmunity, CellularInjections, SubcutaneousInterferon-gammaInterleukin-12Leishmania majorLeishmaniasis, CutaneousLymph NodesLymphocyte ActivationMiceMice, Inbred BALB CMice, TransgenicProtein Kinase CProtozoan ProteinsReceptors, InterleukinReceptors, Interleukin-12Th1 CellsVaccines, DNAConceptsIFN-gamma-producing T cellsDepletion of CD8DNA-vaccinated miceT cellsDNA vaccinationProtective immunityImmunoregulatory roleWk postvaccinationLong-term protective immunityLACK-specific CD4Time of vaccinationPotential immunoregulatory roleNovel immunoregulatory roleTh1 immunityIL-12Th1 cellsInfectious challengeCD8VaccinationInfectionLeishmania majorStriking decreaseMiceImmunityPostvaccination