2021
A humanized mouse model of chronic COVID-19
Sefik E, Israelow B, Mirza H, Zhao J, Qu R, Kaffe E, Song E, Halene S, Meffre E, Kluger Y, Nussenzweig M, Wilen CB, Iwasaki A, Flavell RA. A humanized mouse model of chronic COVID-19. Nature Biotechnology 2021, 40: 906-920. PMID: 34921308, PMCID: PMC9203605, DOI: 10.1038/s41587-021-01155-4.Peer-Reviewed Original ResearchConceptsChronic COVID-19Humanized mouse modelImmune responseMouse modelAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSyndrome coronavirus 2 infectionCOVID-19Adaptive human immune responsesInterferon-stimulated gene signaturePersistent viral RNACoronavirus 2 infectionPatient-derived antibodiesT-cell lymphopeniaHuman immune responseHyperactive immune responseCoronavirus disease 2019Inflammatory macrophage responseImmunological injuryLung pathologyCell lymphopeniaDisease 2019Severe diseaseRodent modelsInflammatory macrophagesA stem-loop RNA RIG-I agonist protects against acute and chronic SARS-CoV-2 infection in mice
Mao T, Israelow B, Lucas C, Vogels CBF, Gomez-Calvo ML, Fedorova O, Breban MI, Menasche BL, Dong H, Linehan M, Alpert T, Anderson F, Earnest R, Fauver J, Kalinich C, Munyenyembe K, Ott I, Petrone M, Rothman J, Watkins A, Wilen C, Landry M, Grubaugh N, Pyle A, Iwasaki A. A stem-loop RNA RIG-I agonist protects against acute and chronic SARS-CoV-2 infection in mice. Journal Of Experimental Medicine 2021, 219: e20211818. PMID: 34757384, PMCID: PMC8590200, DOI: 10.1084/jem.20211818.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionChronic SARS-CoV-2 infectionVariants of concernLethal SARS-CoV-2 infectionPost-infection therapyLower respiratory tractPost-exposure treatmentType I interferonSARS-CoV-2Effective medical countermeasuresAdaptive immune systemBroad-spectrum antiviralsContext of infectionSingle doseRespiratory tractViral controlImmunodeficient miceSevere diseaseMouse modelI interferonViral infectionImmune systemInnate immunityDisease preventionConsiderable efficacyAdaptive 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
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 diseaseMiceConventional type 2 dendritic cells and natural killer cells mediate control of early metastatic seeding
Weizman O, Krykbaeva I, Bosenburg M, Iwasaki A. Conventional type 2 dendritic cells and natural killer cells mediate control of early metastatic seeding. The Journal Of Immunology 2020, 204: 88.17-88.17. DOI: 10.4049/jimmunol.204.supp.88.17.Peer-Reviewed Original ResearchConventional type 2 dendritic cellsType 2 dendritic cellsImmune cellsMetastatic burdenNK cellsDendritic cellsIntracardiac injectionHost anti-tumor immunityType I IFN-independent mannerAdaptive immune cellsAnti-tumor immunityLocal immune cellsNatural killer cellsSyngeneic mouse modelIFN-independent mannerEarly metastatic seedingMetastatic controlTranscription factor IRF3Killer cellsPrimary tumorMetastatic spreadInnate sensorsMouse modelMetastatic growthMetastatic seedingVEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours
Song E, Mao T, Dong H, Boisserand LSB, Antila S, Bosenberg M, Alitalo K, Thomas JL, Iwasaki A. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature 2020, 577: 689-694. PMID: 31942068, PMCID: PMC7100608, DOI: 10.1038/s41586-019-1912-x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain NeoplasmsCD8-Positive T-LymphocytesCell Cycle CheckpointsCell Line, TumorCell MovementCentral Nervous SystemCross-PrimingFemaleGlioblastomaHEK293 CellsHumansImmunologic MemoryImmunologic SurveillanceLymph NodesLymphangiogenesisLymphatic VesselsMaleMelanomaMeningesMiceMice, Inbred C57BLProgrammed Cell Death 1 ReceptorVascular Endothelial Growth Factor CConceptsCD8 T cellsCentral nervous systemT cellsImmune responseBrain tumorsImmune surveillanceLymphatic drainageNervous systemAntigen-specific immune responsesDeep cervical lymph nodesCapacity of VEGFCervical lymph nodesCheckpoint blockade therapyMeningeal lymphatic systemVascular endothelial growth factor CNew therapeutic approachesUncontrolled tumor growthMeningeal lymphatic vasculatureBlockade therapyLymph nodesTherapeutic approachesMouse modelTumor growthMemory responsesTumors
2019
Effector TH17 Cells Give Rise to Long-Lived TRM Cells that Are Essential for an Immediate Response against Bacterial Infection
Vesely M, Pallis P, Bielecki P, Low JS, Zhao J, Harman CCD, Kroehling L, Jackson R, Bailis W, Licona-Limón P, Xu H, Iijima N, Pillai PS, Kaplan DH, Weaver CT, Kluger Y, Kowalczyk MS, Iwasaki A, Pereira JP, Esplugues E, Gagliani N, Flavell RA. Effector TH17 Cells Give Rise to Long-Lived TRM Cells that Are Essential for an Immediate Response against Bacterial Infection. Cell 2019, 178: 1176-1188.e15. PMID: 31442406, PMCID: PMC7057720, DOI: 10.1016/j.cell.2019.07.032.Peer-Reviewed Original ResearchConceptsCD4 TTissue-resident memory T cellsBacterial infectionsResident memory T cellsFunction of airwayLife-long protectionEffector memory TMemory T cellsTh17 cellsTRM cellsΓδ TEffector cellsMemory TBacterial clearanceT cellsIL-7Adaptive immunityMouse modelMemory responsesVaccine designHost defenseLymphatic endothelial cellsDepletion studiesEndothelial cellsCellular origin
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 activity
2016
Type 1 Interferon Regulates Inflammation Associated RBC Alloimmunization By Promoting Monocyte-Derived Dendritic Cell Erythrophagocytosis in Mice
Gibb D, Natarajan P, Liu J, Santhanakrishnan M, Iwasaki A, Hendrickson J. Type 1 Interferon Regulates Inflammation Associated RBC Alloimmunization By Promoting Monocyte-Derived Dendritic Cell Erythrophagocytosis in Mice. Blood 2016, 128: 19. DOI: 10.1182/blood.v128.22.19.19.Peer-Reviewed Original ResearchMonocyte-derived dendritic cellsReactivity of seraPeak antibody responseWT miceIfnar1-/- miceType 1 interferonDendritic cellsRBC transfusionPeripheral bloodAntibody responseRBC alloimmunizationAlloimmune responseSpecific IgGIgG antibodiesInflammatory diseasesMouse modelRBC antigensIndividual miceCCR2-/- miceFrequency of alloimmunizationHuman KEL glycoproteinFlow cytometric crossmatchActivation marker expressionDendritic cell activationRole of inflammationVaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection
Yockey LJ, Varela L, Rakib T, Khoury-Hanold W, Fink SL, Stutz B, Szigeti-Buck K, Van den Pol A, Lindenbach BD, Horvath TL, Iwasaki A. Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection. Cell 2016, 166: 1247-1256.e4. PMID: 27565347, PMCID: PMC5006689, DOI: 10.1016/j.cell.2016.08.004.Peer-Reviewed Original ResearchMeSH KeywordsAbortion, HabitualAnimalsBrainBrain DiseasesDisease Models, AnimalFemaleFetal Growth RetardationInterferon Regulatory Factor-3MiceMice, Inbred C57BLMice, Mutant StrainsPregnancyPregnancy Complications, InfectiousReceptor, Interferon alpha-betaVaginaVirus ReplicationZika VirusZika Virus InfectionConceptsZika virusFetal brain infectionFetal growth restrictionLocal viral replicationWild-type miceType I interferon receptorZIKV challengeTranscription factor IRF3Vaginal exposureGenital mucosaBrain infectionWT miceEarly pregnancyZIKV infectionGrowth restrictionPregnant damsVaginal infectionsZIKV replicationFetal brainMouse modelIFN pathwayVaginal tractUnborn fetusViral replicationDisease consequencesViral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality
Khoury-Hanold W, Yordy B, Kong P, Kong Y, Ge W, Szigeti-Buck K, Ralevski A, Horvath TL, Iwasaki A. Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality. Cell Host & Microbe 2016, 19: 788-799. PMID: 27281569, PMCID: PMC4902295, DOI: 10.1016/j.chom.2016.05.008.Peer-Reviewed Original ResearchConceptsGenital HSV-1 infectionEnteric nervous systemHSV-1 infectionSensory nervous systemNervous systemGenital herpesToxic megacolonHSV-1Genital mucosal epithelial cellsPeripheral sensory nervous systemDorsal root gangliaPathological inflammatory responsesMucosal epithelial cellsHerpes simplex virus 1Simplex virus 1Urinary retentionEnteric neuronsLaxative treatmentAutonomic gangliaRoot gangliaInflammatory responseViral gene transcriptionMouse modelInfectionEpithelial cells
2014
Poliomyelitis in transgenic mice expressing CD155 under the control of the Tage4 promoter after oral and parenteral poliovirus inoculation
Khan S, Toyoda H, Linehan M, Iwasaki A, Nomoto A, Bernhardt G, Cello J, Wimmer E. Poliomyelitis in transgenic mice expressing CD155 under the control of the Tage4 promoter after oral and parenteral poliovirus inoculation. Journal Of General Virology 2014, 95: 1668-1676. PMID: 24784416, PMCID: PMC4103066, DOI: 10.1099/vir.0.064535-0.Peer-Reviewed Original ResearchConceptsTg mouse modelPeyer's patchesOral routeGastrointestinal tractMouse modelTransgenic miceImmunocompetent transgenic mouseHuman PV receptorCD155 tg miceSurface of enterocytesTgPVR21 miceCD155 expressionParenteral inoculationTg miceIntracerebral inoculationOral infectionYoung miceGut infectionLymphatic tissueGerminal centersPV infectionPV replicationPV receptorSmall intestineHuman CD155
2008
T helper dependent CTL migration into the vaginal mucosa
Nakanishi Y, Lu B, Gerard C, Iwasaki A. T helper dependent CTL migration into the vaginal mucosa. The FASEB Journal 2008, 22: 852.5-852.5. DOI: 10.1096/fasebj.22.1_supplement.852.5.Peer-Reviewed Original ResearchCD4 helpCTL migrationVaginal mucosaIFN-inducible chemokinesIFN-γ productionSecretion of IFNChemokine receptor CXCR3Site of infectionAntiviral host defenseMucosal sitesChemokine secretionReceptor CXCR3T helpT lymphocytesVirus infectionVaginal epitheliumHelpless miceMouse modelMucosal tissuesHost defenseVirus 2InfectionInfection siteMucosaSecretion
2004
In Vivo Role of Nectin-1 in Entry of Herpes Simplex Virus Type 1 (HSV-1) and HSV-2 through the Vaginal Mucosa
Linehan MM, Richman S, Krummenacher C, Eisenberg RJ, Cohen GH, Iwasaki A. In Vivo Role of Nectin-1 in Entry of Herpes Simplex Virus Type 1 (HSV-1) and HSV-2 through the Vaginal Mucosa. Journal Of Virology 2004, 78: 2530-2536. PMID: 14963155, PMCID: PMC369262, DOI: 10.1128/jvi.78.5.2530-2536.2004.Peer-Reviewed Original ResearchConceptsHSV-2HSV-1Viral entryNectin-1Genital herpesGenital mucosaVaginal epitheliumVaginal mucosaHerpes simplex virus type 2Simplex virus type 2Primary genital herpesHerpes simplex virus type 1Mouse vaginal epitheliumFemale genital tractSimplex virus type 1Virus type 1Virus type 2Intravaginal inoculationHSV infectionMenstrual cycleVaginal infectionsGenital tractMouse modelEstrous cycleType 2