2022
Endogenous Retroviruses Provide Protection Against Vaginal HSV-2 Disease
Jayewickreme R, Mao T, Philbrick W, Kong Y, Treger RS, Lu P, Rakib T, Dong H, Dang-Lawson M, Guild WA, Lau TJ, Iwasaki A, Tokuyama M. Endogenous Retroviruses Provide Protection Against Vaginal HSV-2 Disease. Frontiers In Immunology 2022, 12: 758721. PMID: 35058919, PMCID: PMC8764156, DOI: 10.3389/fimmu.2021.758721.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEndogenous RetrovirusesFemaleHerpes GenitalisHerpesvirus 2, HumanMiceMice, KnockoutVaginal DiseasesConceptsHSV-2 infectionHSV-2 diseaseHerpes simplex virus type 2 infectionSimplex virus type 2 infectionEnhanced type I interferonIntravaginal HSV-2 infectionVaginal HSV-2 infectionVirus type 2 infectionEndogenous retrovirusesReceptor-deficient miceType 2 infectionHigh systemic levelsWildtype C57BL/6 miceType I interferonTLR7-/- miceC57BL/6 miceInfectious endogenous retrovirusDeficient miceIntravaginal applicationAntiviral immunityI interferonVaginal tissueDetrimental functionsTLR7Mice
2021
Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA
Oh JE, Song E, Moriyama M, Wong P, Zhang S, Jiang R, Strohmeier S, Kleinstein SH, Krammer F, Iwasaki A. Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA. Science Immunology 2021, 6: eabj5129. PMID: 34890255, PMCID: PMC8762609, DOI: 10.1126/sciimmunol.abj5129.Peer-Reviewed Original ResearchConceptsVirus infectionIgA secretionB cellsMucosal surfacesIgA-secreting B cellsIgA-expressing cellsRole of IgARespiratory virus infectionsIgA-secreting cellsLower respiratory tractInfluenza virus infectionEffective immune protectionHeterologous virus infectionMemory B cellsSecretory immunoglobulin AProtein-based vaccinesB cell populationsPredominant Ig isotypeSite of entryIntranasal primingBronchoalveolar spaceProtective immunityVaccine strategiesRespiratory mucosaImmune protectionKDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements
Zhang SM, Cai WL, Liu X, Thakral D, Luo J, Chan LH, McGeary MK, Song E, Blenman KRM, Micevic G, Jessel S, Zhang Y, Yin M, Booth CJ, Jilaveanu LB, Damsky W, Sznol M, Kluger HM, Iwasaki A, Bosenberg MW, Yan Q. KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements. Nature 2021, 598: 682-687. PMID: 34671158, PMCID: PMC8555464, DOI: 10.1038/s41586-021-03994-2.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorDNA-Binding ProteinsEpigenesis, GeneticGene SilencingHeterochromatinHistone-Lysine N-MethyltransferaseHumansInterferon Type IJumonji Domain-Containing Histone DemethylasesMaleMelanomaMiceMice, Inbred C57BLMice, KnockoutNuclear ProteinsRepressor ProteinsRetroelementsTumor EscapeConceptsImmune checkpoint blockadeImmune evasionCheckpoint blockadeImmune responseAnti-tumor immune responseRobust adaptive immune responseTumor immune evasionAnti-tumor immunityAdaptive immune responsesType I interferon responseDNA-sensing pathwayMouse melanoma modelImmunotherapy resistanceMost patientsCurrent immunotherapiesTumor immunogenicityImmune memoryMelanoma modelCytosolic RNA sensingRole of KDM5BConsiderable efficacyInterferon responseImmunotherapyEpigenetic therapyBlockadeAdaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2
Israelow B, Mao T, Klein J, Song E, Menasche B, Omer SB, Iwasaki A. Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2. Science Immunology 2021, 6: eabl4509. PMID: 34623900, PMCID: PMC9047536, DOI: 10.1126/sciimmunol.abl4509.Peer-Reviewed Original ResearchConceptsSARS-CoV-2Viral clearanceImmune determinantsMouse modelSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Cellular adaptive immunitySyndrome coronavirus 2Vivo protective capacityVariants of concernMRNA vaccinationHomologous infectionCellular immunityConvalescent miceCoronavirus 2Antibody responsePrimary infectionEffective vaccineAdaptive immunityConfer protectionInfectionNatural infectionProtective capacityClearance
2020
m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development
Gao Y, Vasic R, Song Y, Teng R, Liu C, Gbyli R, Biancon G, Nelakanti R, Lobben K, Kudo E, Liu W, Ardasheva A, Fu X, Wang X, Joshi P, Lee V, Dura B, Viero G, Iwasaki A, Fan R, Xiao A, Flavell RA, Li HB, Tebaldi T, Halene S. m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development. Immunity 2020, 52: 1007-1021.e8. PMID: 32497523, PMCID: PMC7408742, DOI: 10.1016/j.immuni.2020.05.003.Peer-Reviewed Original ResearchConceptsDouble-stranded RNADeleterious innate immune responseMammalian hematopoietic developmentEndogenous double-stranded RNAHematopoietic developmentInnate immune responseAbundant RNA modificationMurine fetal liverPattern recognition receptor pathwaysImmune responseProtein codingDsRNA formationRNA modificationsWriter METTL3Hematopoietic defectsPerinatal lethalityNative stateConditional deletionAberrant innate immune responsesLoss of METTL3Hematopoietic failureReceptor pathwayAberrant immune responsePrevents formationFetal liver
2019
Ketogenic diet activates protective γδ T cell responses against influenza virus infection
Goldberg EL, Molony RD, Kudo E, Sidorov S, Kong Y, Dixit VD, Iwasaki A. Ketogenic diet activates protective γδ T cell responses against influenza virus infection. Science Immunology 2019, 4 PMID: 31732517, PMCID: PMC7189564, DOI: 10.1126/sciimmunol.aav2026.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDiet, KetogenicInfluenza A virusMiceMice, Inbred C57BLMice, KnockoutOrthomyxoviridae InfectionsT-LymphocytesConceptsΓδ T cellsKetogenic dietIAV infectionT cellsGlobal health care concernHigh-fat ketogenic dietΓδ T cell responsesInfection-associated morbidityLethal IAV infectionT cell responsesInfluenza virus infectionHealth care concernHigh-carbohydrate dietInfluenza diseaseKD feedingVirus infectionNew therapiesAntiviral resistanceHepatic ketogenesisCare concernsCell responsesInfectionBarrier functionDietMetabolic adaptationHuman APOBEC3G Prevents Emergence of Infectious Endogenous Retrovirus in Mice
Treger RS, Tokuyama M, Dong H, Salas-Briceno K, Ross SR, Kong Y, Iwasaki A. Human APOBEC3G Prevents Emergence of Infectious Endogenous Retrovirus in Mice. Journal Of Virology 2019, 93: 10.1128/jvi.00728-19. PMID: 31341050, PMCID: PMC6798113, DOI: 10.1128/jvi.00728-19.Peer-Reviewed Original ResearchConceptsToll-like receptor 7Infectious endogenous retrovirusHuman APOBEC3GAPOBEC3GHA3GEndogenous retrovirusesAntiviral restriction factorsReceptor 7Human endogenous retrovirusesTransgenic miceERV RNAsERV reactivationMiceAPOBEC3 proteinsCell-intrinsic defenseHost mechanismsPrevents emergenceRestriction factorsPermissive cellsDeleterious consequencesSubsequent disruptionRetrovirusesEctopic expressionHumansExpressionThe Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer
Lee JW, Zhang Y, Eoh KJ, Sharma R, Sanmamed MF, Wu J, Choi J, Park HS, Iwasaki A, Kaftan E, Chen L, Papadimitrakopoulou V, Herbst RS, Koo JS. The Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer. Journal Of Thoracic Oncology 2019, 14: 1046-1060. PMID: 30771521, PMCID: PMC6542636, DOI: 10.1016/j.jtho.2019.02.004.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinoma of LungAnimalsAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsB7-H1 AntigenDrug SynergismFemaleLung NeoplasmsMAP Kinase Kinase KinasesMiceMice, KnockoutMice, TransgenicMyeloid-Derived Suppressor CellsProgrammed Cell Death 1 ReceptorProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)PyridonesPyrimidinonesSurvival AnalysisTumor Suppressor Protein p53ConceptsImmune cell populationsLung tumorsMEK inhibitorsDeath-1Survival outcomesLung cancerL1 mAbsTumor-infiltrating immune cell populationsTumor-infiltrating immune cellsCell death ligand 1Flow cytometryLung cancer mouse modelAdenoviral Cre recombinaseAutochthonous lung tumorsImmunomodulatory monoclonal antibodiesTumor-infiltrating CD8PD-L1 expressionSingle-agent therapyTumor-bearing lungsDeath ligand 1Tumor-free miceLung cancer modelCombinatorial antitumor effectCancer mouse modelCell populationsThe Lupus Susceptibility Locus Sgp3 Encodes the Suppressor of Endogenous Retrovirus Expression SNERV
Treger RS, Pope SD, Kong Y, Tokuyama M, Taura M, Iwasaki A. The Lupus Susceptibility Locus Sgp3 Encodes the Suppressor of Endogenous Retrovirus Expression SNERV. Immunity 2019, 50: 334-347.e9. PMID: 30709743, PMCID: PMC6382577, DOI: 10.1016/j.immuni.2018.12.022.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsEndogenous RetrovirusesGene Expression RegulationGenetic Predisposition to DiseaseGlycoproteinsHEK293 CellsHumansLupus Erythematosus, SystemicLupus NephritisMiceMice, 129 StrainMice, Inbred C57BLMice, Inbred NZBMice, KnockoutMolecular ChaperonesNuclear ProteinsRepressor Proteins
2018
The interaction between IKKα and LC3 promotes type I interferon production through the TLR9-containing LAPosome
Hayashi K, Taura M, Iwasaki A. The interaction between IKKα and LC3 promotes type I interferon production through the TLR9-containing LAPosome. Science Signaling 2018, 11 PMID: 29717061, PMCID: PMC6462218, DOI: 10.1126/scisignal.aan4144.Peer-Reviewed Original ResearchConceptsInterferon regulatory factor 7Autophagy protein LC3Type I IFN productionI interferonI IFN productionMicrotubule-associated proteinsPutative LC3Type I interferon productionEndosomal vesiclesAutophagosome formationNoncanonical autophagyToll-like receptor 9Production of IFNStimulation of TLR9Regulatory factor 7Protein LC3Direct bindingI interferon productionIFN productionEndosomesChain 3Type I interferonKinase IKKαLC3Lap formationA minimal RNA ligand for potent RIG-I activation in living mice
Linehan MM, Dickey TH, Molinari ES, Fitzgerald ME, Potapova O, Iwasaki A, Pyle AM. A minimal RNA ligand for potent RIG-I activation in living mice. Science Advances 2018, 4: e1701854. PMID: 29492454, PMCID: PMC5821489, DOI: 10.1126/sciadv.1701854.Peer-Reviewed Original ResearchConceptsStem-loop RNAInterferon-stimulated genesImmune systemPotent synthetic activatorVertebrate immune systemType I interferonInnate immune systemRIG-I receptorRIG-I activationExpression networksRemodeling factorsPotent RIGRNA sequencingSpecific genesRNA ligandsI interferonAntiviral defenseInterferon responseRNA sensorsPolycytidylic acidSynthetic activatorsMiceInterferonGenesRNA
2017
Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice
Jurado KA, Yockey LJ, Wong PW, Lee S, Huttner AJ, Iwasaki A. Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice. Nature Microbiology 2017, 3: 141-147. PMID: 29158604, PMCID: PMC5780207, DOI: 10.1038/s41564-017-0060-z.Peer-Reviewed Original ResearchConceptsCentral nervous systemZIKV infectionZika virusT cellsNeurological complicationsNervous systemBlood-brain barrier breakdownAntiviral CD8 T cellsHigh viral burdenIFNAR knockout miceCD8 T cellsEffector T cellsSusceptible mouse modelBlood-brain barrierNon-haematopoietic cellsSite of infectionIFNAR1 deficiencyViral burdenNeurological manifestationsGuillain-BarréBarrier breakdownMouse modelKnockout miceAstrocytes resultsAntiviral activityIRE1α 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 IZika virus causes testicular atrophy
Uraki R, Hwang J, Jurado KA, Householder S, Yockey LJ, Hastings AK, Homer RJ, Iwasaki A, Fikrig E. Zika virus causes testicular atrophy. Science Advances 2017, 3: e1602899. PMID: 28261663, PMCID: PMC5321463, DOI: 10.1126/sciadv.1602899.Peer-Reviewed Original ResearchConceptsZika virusTesticular atrophyAcute viremic phaseZIKV-infected miceMosquito-borne flavivirusTestosterone-producing Leydig cellsProgressive testicular atrophyZIKV persistenceFetal infectionViremic phaseNeonatal abnormalitiesSerum testosteroneZIKV infectionNeurological dysfunctionSubcutaneous injectionZIKV replicationLeydig cellsVirus replicationVertical transmissionEpithelial cellsMiceViral RNAReproductive deficienciesAtrophyMale fertility
2016
CD301b+ dendritic cells stimulate tissue-resident memory CD8+ T cells to protect against genital HSV-2
Shin H, Kumamoto Y, Gopinath S, Iwasaki A. CD301b+ dendritic cells stimulate tissue-resident memory CD8+ T cells to protect against genital HSV-2. Nature Communications 2016, 7: 13346. PMID: 27827367, PMCID: PMC5105190, DOI: 10.1038/ncomms13346.Peer-Reviewed Original ResearchConceptsCD8 TRM cellsAntigen-presenting cellsGenital HSV-2 infectionTissue-resident memory CD8HSV-2 infectionTRM cellsDendritic cellsMemory CD8Protective immunityT cellsPopulations of APCsGenital HSV-2Protective immune responseFemale genital tractMHC class IHSV-2Genital tractAntigen presentationImmune responseLamina propriaViral infectionConfer protectionBarrier tissuesClass IInfectionAXL 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
2015
Candida albicans Morphology and Dendritic Cell Subsets Determine T Helper Cell Differentiation
Kashem SW, Igyártó B, Gerami-Nejad M, Kumamoto Y, Mohammed J, Jarrett E, Drummond RA, Zurawski SM, Zurawski G, Berman J, Iwasaki A, Brown GD, Kaplan DH. Candida albicans Morphology and Dendritic Cell Subsets Determine T Helper Cell Differentiation. Immunity 2015, 42: 356-366. PMID: 25680275, PMCID: PMC4343045, DOI: 10.1016/j.immuni.2015.01.008.Peer-Reviewed Original ResearchConceptsT helper cell responsesHelper cell responsesCell responsesInterleukin-6Systemic infectionDectin-1 ligationTh1 cell responsesTh cell responsesT helper 17 (Th17) cell differentiationT helper cell differentiationTissue-specific protectionSkin infection modelMurine skin infection modelC. albicansHelper cell differentiationMucocutaneous immunityCutaneous infectionsVaccine strategiesLangerhans cellsSystemic immunityT cellsCell differentiationInfection modelInfectionImmunity
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 typeInductionCellsActivation
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 virusNitric Oxide and TNFα Are Critical Regulators of Reversible Lymph Node Vascular Remodeling and Adaptive Immune Response
Sellers SL, Iwasaki A, Payne GW. Nitric Oxide and TNFα Are Critical Regulators of Reversible Lymph Node Vascular Remodeling and Adaptive Immune Response. PLOS ONE 2013, 8: e60741. PMID: 23573281, PMCID: PMC3616017, DOI: 10.1371/journal.pone.0060741.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAnimalsArteriolesCell DegranulationChlorocebus aethiopsFemaleHerpes SimplexLymph NodesMast CellsMiceMice, 129 StrainMice, Inbred C57BLMice, KnockoutNeovascularization, PhysiologicNG-Nitroarginine Methyl EsterNifedipineNitric OxideNitric Oxide Synthase Type IIIPhenylephrineTumor Necrosis Factor-alphaVasoconstrictionVasodilator AgentsVero CellsConceptsAdaptive immune responsesEndothelial nitric oxide synthaseImmune responseVascular remodelingHerpes simplex type II infectionT cell-dependent mechanismGenetic ablation modelCell-dependent mechanismNitric oxide levelsType II infectionNitric oxide synthaseCourse of infectionInguinal LNsLN cellularityVascular eventsVascular changesArteriole diameterPharmacological blockadeMain arterioleOxide synthaseTNFα expressionMast cellsOxide levelsViral infectionIntravital microscopy