2022
Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion
Vora SM, Fontana P, Mao T, Leger V, Zhang Y, Fu TM, Lieberman J, Gehrke L, Shi M, Wang L, Iwasaki A, Wu H. Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2117198119. PMID: 35149555, PMCID: PMC8892331, DOI: 10.1073/pnas.2117198119.Peer-Reviewed Original ResearchConceptsSARS-CoV-2SARS-CoV-2 nonstructural protein 1Host protein synthesisSARS-CoV-2 5Nonstructural protein 1Viral translationNucleic acid antisenseAntiviral immunityProtein synthesisTherapeutic targetTransgenic miceViral protein synthesisViral replicationDrug resistanceHuman ACE2Infected cellsProtein 1COVID-19Virulence mechanismsNanomolar concentrationsHost translationPathogenic virusesEntry channelSuppressionTranslational suppression
2020
RUNX Binding Sites Are Enriched in Herpesvirus Genomes, and RUNX1 Overexpression Leads to Herpes Simplex Virus 1 Suppression
Kim DJ, Khoury-Hanold W, Jain PC, Klein J, Kong Y, Pope SD, Ge W, Medzhitov R, Iwasaki A. RUNX Binding Sites Are Enriched in Herpesvirus Genomes, and RUNX1 Overexpression Leads to Herpes Simplex Virus 1 Suppression. Journal Of Virology 2020, 94: 10.1128/jvi.00943-20. PMID: 32878886, PMCID: PMC7592204, DOI: 10.1128/jvi.00943-20.Peer-Reviewed Original ResearchConceptsDorsal root gangliaHSV-1 infectionNumerous viral genesHSV-2Sensory neuronsHost transcription factorsHSV-1 genomeHSV-1Dorsal root ganglion neuronsViral gene expressionMouse DRG neuronsLifelong latent infectionViral genesKnockdown of RUNX1Herpes simplex virus 1Simplex virus 1DRG neuronsGanglion neuronsRoot gangliaOverall infectionViral gene transcriptionLatent infectionHSV-2 genomeInfectionNeuroblastoma cellsDetection of SARS-CoV-2 RNA by multiplex RT-qPCR
Kudo E, Israelow B, Vogels CBF, Lu P, Wyllie AL, Tokuyama M, Venkataraman A, Brackney DE, Ott IM, Petrone ME, Earnest R, Lapidus S, Muenker MC, Moore AJ, Casanovas-Massana A, Team Y, Omer SB, Dela Cruz CS, Farhadian SF, Ko AI, Grubaugh ND, Iwasaki A. Detection of SARS-CoV-2 RNA by multiplex RT-qPCR. PLOS Biology 2020, 18: e3000867. PMID: 33027248, PMCID: PMC7571696, DOI: 10.1371/journal.pbio.3000867.Peer-Reviewed Original ResearchMeSH KeywordsBetacoronavirusCase-Control StudiesClinical Laboratory TechniquesCoronavirus InfectionsCOVID-19COVID-19 TestingDNA PrimersHEK293 CellsHumansLimit of DetectionMultiplex Polymerase Chain ReactionNasopharynxPandemicsPneumonia, ViralReagent Kits, DiagnosticReverse Transcriptase Polymerase Chain ReactionRNA, ViralSARS-CoV-2United StatesConceptsSARS-CoV-2 RNAMultiplex RT-qPCRRT-qPCRSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testingSARS-CoV-2Quantitative reverse transcription PCRCycle threshold valuesReverse transcription-PCRRT-qPCR assaysDisease controlMultiplex RT-qPCR assayTranscription-PCRAssaysSingle assayLow copy numberVEGF-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
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 virusCellsOverhangMoleculesSignalingRIG-I Selectively Discriminates against 5′-Monophosphate RNA
Ren X, Linehan MM, Iwasaki A, Pyle AM. RIG-I Selectively Discriminates against 5′-Monophosphate RNA. Cell Reports 2019, 26: 2019-2027.e4. PMID: 30784585, DOI: 10.1016/j.celrep.2019.01.107.Peer-Reviewed Original ResearchThe 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
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 typesThe 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
Sensing Self and Foreign Circular RNAs by Intron Identity
Chen YG, Kim MV, Chen X, Batista PJ, Aoyama S, Wilusz JE, Iwasaki A, Chang HY. Sensing Self and Foreign Circular RNAs by Intron Identity. Molecular Cell 2017, 67: 228-238.e5. PMID: 28625551, PMCID: PMC5610545, DOI: 10.1016/j.molcel.2017.05.022.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceDEAD Box Protein 58Encephalitis Virus, Venezuelan EquineEncephalomyelitis, Venezuelan EquineHEK293 CellsHeLa CellsHost-Pathogen InteractionsHumansImmune ToleranceImmunity, InnateIntronsMiceNucleic Acid ConformationProtein BindingRAW 264.7 CellsReceptors, ImmunologicRNARNA Processing, Post-TranscriptionalRNA, CircularRNA, MessengerRNA-Binding ProteinsSpliceosomesTransfectionConceptsCircular RNAsInnate immunity genesMammalian transcriptionDiverse RNACytoplasmic fociHuman circRNAsMammalian cellsImmunity genesEndogenous splicingHuman intronsInnate immune sensingPrimary sequenceCircRNA sequenceRNA structureCircRNAsUnknown functionIntronsRNASensor RIGImmune sensingInnate immunitySelf-nonself discriminationPotent inductionSequenceBiogenesis
2014
Alternative 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 TransductionT-LymphocytesTime FactorsTransfectionConceptsMitogen-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 functionCells
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 virus