2024
Compartmentalized ocular lymphatic system mediates eye–brain immunity
Yin X, Zhang S, Lee J, Dong H, Mourgkos G, Terwilliger G, Kraus A, Geraldo L, Poulet M, Fischer S, Zhou T, Mohammed F, Zhou J, Wang Y, Malloy S, Rohner N, Sharma L, Salinas I, Eichmann A, Thomas J, Saltzman W, Huttner A, Zeiss C, Ring A, Iwasaki A, Song E. Compartmentalized ocular lymphatic system mediates eye–brain immunity. Nature 2024, 628: 204-211. PMID: 38418880, PMCID: PMC10990932, DOI: 10.1038/s41586-024-07130-8.Peer-Reviewed Original ResearchResponse to herpes simplex virusCentral nervous systemImmune response to herpes simplex virusPosterior eyeImmune responseTherapeutic immune responsesOptic nerve sheathCervical lymph nodesAdeno-associated virusCNS diseaseDeep cervical lymph nodesHerpes simplex virusImmune protected miceCentral nervous system tissueLymphatic drainage systemImmunological featuresAnatomical extensionNerve sheathOptic nerveGene therapyLymph nodesMultiple dosesSimplex virusLymphatic circuitLymphatic signal
2023
Cancer Relevance of Circulating Antibodies Against LINE-1 Antigens in Humans
Vylegzhanina A, Bespalov I, Novototskaya-Vlasova K, Hall B, Gleiberman A, Yu H, Leontieva O, Leonova K, Kurnasov O, Osterman A, Dy G, Komissarov A, Vasilieva E, Gehlhausen J, Iwasaki A, Ambrosone C, Tsuji T, Matsuzaki J, Odunsi K, Andrianova E, Gudkov A. Cancer Relevance of Circulating Antibodies Against LINE-1 Antigens in Humans. Cancer Research Communications 2023, 3: 2256-2267. PMID: 37870410, PMCID: PMC10631453, DOI: 10.1158/2767-9764.crc-23-0289.Peer-Reviewed Original ResearchConceptsL1 antigenCancer typesDisease stage 1Discovery of autoantibodiesHigh IgG titersTumor-associated antigensDetermination of immunoreactivityTumor immunoreactivityCirculating AntibodiesIgG titersAntibody responseImmune responseLiver cancerReactive IgGHealthy individualsCurable cancer typesImmune systemAntigenNormal tissuesPatientsCancerEarly detectionElevated levelsCarcinogenic processAutoantibodiesSARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC)
Proal A, VanElzakker M, Aleman S, Bach K, Boribong B, Buggert M, Cherry S, Chertow D, Davies H, Dupont C, Deeks S, Eimer W, Ely E, Fasano A, Freire M, Geng L, Griffin D, Henrich T, Iwasaki A, Izquierdo-Garcia D, Locci M, Mehandru S, Painter M, Peluso M, Pretorius E, Price D, Putrino D, Scheuermann R, Tan G, Tanzi R, VanBrocklin H, Yonker L, Wherry E. SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC). Nature Immunology 2023, 24: 1616-1627. PMID: 37667052, DOI: 10.1038/s41590-023-01601-2.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 reservoirPost-acute sequelaeImmune responseHost immune responseCoronavirus SARS-CoV-2COVID-19SARS-CoV-2Neuroimmune abnormalitiesAcute infectionLong COVIDClinical trialsViral RNAMillions of peopleSequelaeFurther studiesViral proteinsPathologyResearch prioritiesRNA/proteinBiological factorsPASCAntiviralsInfectionAbnormalitiesTrialsPD-1highCXCR5–CD4+ peripheral helper T cells promote CXCR3+ plasmablasts in human acute viral infection
Asashima H, Mohanty S, Comi M, Ruff W, Hoehn K, Wong P, Klein J, Lucas C, Cohen I, Coffey S, Lele N, Greta L, Raddassi K, Chaudhary O, Unterman A, Emu B, Kleinstein S, Montgomery R, Iwasaki A, Dela Cruz C, Kaminski N, Shaw A, Hafler D, Sumida T. PD-1highCXCR5–CD4+ peripheral helper T cells promote CXCR3+ plasmablasts in human acute viral infection. Cell Reports 2023, 42: 111895. PMID: 36596303, PMCID: PMC9806868, DOI: 10.1016/j.celrep.2022.111895.Peer-Reviewed Original ResearchConceptsAcute viral infectionTph cellsViral infectionCXCR3 expressionClinical outcomesHelper TSevere viral infectionsB cell helpBetter clinical outcomesProtective humoral immunityT cell-B cell interactionsKey immune responsesPlasmablast expansionB cell differentiationCell subsetsHumoral immunityCell helpImmune responseInterferon γPlasmablast differentiationB cellsPlasmablastsCell responsesInfectionCD4
2022
The immunology and immunopathology of COVID-19
Merad M, Blish CA, Sallusto F, Iwasaki A. The immunology and immunopathology of COVID-19. Science 2022, 375: 1122-1127. PMID: 35271343, DOI: 10.1126/science.abm8108.Peer-Reviewed Original ResearchConceptsImmune responseAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSyndrome coronavirus 2 infectionFatal COVID-19Coronavirus 2 infectionPost-acute sequelaeCOVID-19 pathophysiologyProlongation of symptomsLong COVID syndromeMajor unmet needCOVID-19SARS-CoV-2COVID syndromeDisease resolutionInflammatory processChronic illnessUnmet needDefinitive findingsImmunology researchCOVID-19 researchImmunopathologySequelaePathophysiologySyndromeSingle-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
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 macrophagesImpact of Chronic HIV Infection on SARS-CoV-2 Infection, COVID-19 Disease and Vaccines
Yang Y, Iwasaki A. Impact of Chronic HIV Infection on SARS-CoV-2 Infection, COVID-19 Disease and Vaccines. Current HIV/AIDS Reports 2021, 19: 5-16. PMID: 34843064, PMCID: PMC8628277, DOI: 10.1007/s11904-021-00590-x.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionSARS-CoV-2Human immune deficiency virus (HIV) infectionSARS-CoV-2 acute infectionImmune systemSevere acute respiratory syndrome coronavirus 2Severe SARS-CoV-2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Chronic HIV infectionSyndrome coronavirus 2Effectiveness of vaccinesHost immune systemCOVID-19 diseaseRecent FindingsPeopleAntiretroviral therapyImmunological changesAcute infectionHIV infectionDisease complicationsPersistent inflammationCoronavirus 2Functional impairmentVirus infectionImmune responseHigh-resolution epitope mapping and characterization of SARS-CoV-2 antibodies in large cohorts of subjects with COVID-19
Haynes WA, Kamath K, Bozekowski J, Baum-Jones E, Campbell M, Casanovas-Massana A, Daugherty PS, Dela Cruz CS, Dhal A, Farhadian SF, Fitzgibbons L, Fournier J, Jhatro M, Jordan G, Klein J, Lucas C, Kessler D, Luchsinger LL, Martinez B, Catherine Muenker M, Pischel L, Reifert J, Sawyer JR, Waitz R, Wunder EA, Zhang M, Iwasaki A, Ko A, Shon J. High-resolution epitope mapping and characterization of SARS-CoV-2 antibodies in large cohorts of subjects with COVID-19. Communications Biology 2021, 4: 1317. PMID: 34811480, PMCID: PMC8608966, DOI: 10.1038/s42003-021-02835-2.Peer-Reviewed Original ResearchConceptsSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2SARS-CoV-2 antibodiesRespiratory syndrome coronavirus 2SARS-CoV-2 epitopesSyndrome coronavirus 2SARS-CoV-2 strainsHigh-resolution epitope mappingCOVID-19SARS-CoV-2SARS-CoV-2 mutantsCoronavirus 2Antibody responseEffective vaccineImmune responseNeutralization activitySevere diseaseLarge cohortEpitope regionsAntibody epitopesEpitope mappingRelated coronavirusesTherapyVaccineViral proteomeKDM5B 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 therapyBlockadeKynurenic 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 malePatientsMalesOutcomesResponseMetabolitesDivergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms
Song E, Bartley CM, Chow RD, Ngo TT, Jiang R, Zamecnik CR, Dandekar R, Loudermilk RP, Dai Y, Liu F, Sunshine S, Liu J, Wu W, Hawes IA, Alvarenga BD, Huynh T, McAlpine L, Rahman NT, Geng B, Chiarella J, Goldman-Israelow B, Vogels CBF, Grubaugh ND, Casanovas-Massana A, Phinney BS, Salemi M, Alexander JR, Gallego JA, Lencz T, Walsh H, Wapniarski AE, Mohanty S, Lucas C, Klein J, Mao T, Oh J, Ring A, Spudich S, Ko AI, Kleinstein SH, Pak J, DeRisi JL, Iwasaki A, Pleasure SJ, Wilson MR, Farhadian SF. Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms. Cell Reports Medicine 2021, 2: 100288. PMID: 33969321, PMCID: PMC8091032, DOI: 10.1016/j.xcrm.2021.100288.Peer-Reviewed Original ResearchNeurological symptomsImmune responseCerebrospinal fluidAnti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodiesCOVID-19Self-reactive immune responsesSARS-CoV-2 antibodiesCompartmentalized immune responseCSF immunoglobulin GRole of autoimmunityCOVID-19 patientsB cell responsesCoronavirus disease 2019Immune surveyNeurologic sequelaePulmonary infectionBrain infectionSerum antibodiesDisease 2019Monoclonal antibody targetsAnimal modelsTarget epitopesCell activationCell responsesSingle-cell RNA sequencingThe first 12 months of COVID-19: a timeline of immunological insights
Carvalho T, Krammer F, Iwasaki A. The first 12 months of COVID-19: a timeline of immunological insights. Nature Reviews Immunology 2021, 21: 245-256. PMID: 33723416, PMCID: PMC7958099, DOI: 10.1038/s41577-021-00522-1.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2Antibodies, ViralAutoantibodiesCOVID-19COVID-19 Drug TreatmentCOVID-19 SerotherapyCOVID-19 VaccinesDexamethasoneDrug DevelopmentGlucocorticoidsHumansImmunization, PassiveImmunologic FactorsInterferon Type IReceptors, CoronavirusSARS-CoV-2Systemic Inflammatory Response SyndromeConceptsSARS-CoV-2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Numerous candidate vaccinesSyndrome coronavirus 2Coronavirus disease 2019Peer-reviewed journalsCandidate vaccinesCoronavirus 2Pneumonia casesDisease 2019Immune responseViral infectionImmunological insightsNovel coronavirusInitial reportCOVID-19First yearMonthsHighlight gapsPreprint serversUnidentified originFuture investigationsVaccineInfectionSex differences in immune responses
Takahashi T, Iwasaki A. Sex differences in immune responses. Science 2021, 371: 347-348. PMID: 33479140, DOI: 10.1126/science.abe7199.Peer-Reviewed Original ResearchConceptsImmune responseCOVID-19Sex differencesSevere COVID-19Risk of deathHigher mortality riskCOVID-19 mortalityPossible biological mechanismsCOVID-19 incidenceMale sexRisk factorsSevere diseaseHigh riskMortality riskMale sex biasOld maleSex-disaggregated dataBehavioral factorsBiological sex differencesDeathVulnerable groupsRiskBiological mechanismsMalesSex
2020
Sex differences in immune responses that underlie COVID-19 disease outcomes
Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, Silva J, Mao T, Oh JE, Tokuyama M, Lu P, Venkataraman A, Park A, Liu F, Meir A, Sun J, Wang EY, Casanovas-Massana A, Wyllie AL, Vogels CBF, Earnest R, Lapidus S, Ott IM, Moore AJ, Shaw A, Fournier J, Odio C, Farhadian S, Dela Cruz C, Grubaugh N, Schulz W, Ring A, Ko A, Omer S, Iwasaki A. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature 2020, 588: 315-320. PMID: 32846427, PMCID: PMC7725931, DOI: 10.1038/s41586-020-2700-3.Peer-Reviewed Original ResearchConceptsInnate immune cytokinesFemale patientsMale patientsImmune cytokinesDisease outcomeImmune responseCOVID-19COVID-19 disease outcomesPoor T cell responsesSARS-CoV-2 infectionSevere acute respiratory syndrome coronavirusAcute respiratory syndrome coronavirusSex-based approachModerate COVID-19Sex differencesRobust T cell activationT cell responsesWorse disease progressionWorse disease outcomesHigher plasma levelsNon-classical monocytesCoronavirus disease 2019T cell activationImmunomodulatory medicationsPlasma cytokinesm6A 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 liverContributions of maternal and fetal antiviral immunity in congenital disease
Yockey LJ, Lucas C, Iwasaki A. Contributions of maternal and fetal antiviral immunity in congenital disease. Science 2020, 368: 608-612. PMID: 32381717, DOI: 10.1126/science.aaz1960.Peer-Reviewed Original ResearchConceptsViral infectionCongenital diseaseDirect viral toxicityMaternal immune responseMaternal immune activationFetal developmental defectsFuture treatment strategiesImmune defense mechanismsPregnancy outcomesFetal demiseImmune activationUncontrolled inflammationMaternal healthChronic infectionTreatment strategiesImmune responseAntiviral immunityRange of syndromesFetal developmentTissue damagePathological effectsInfectionViral toxicityDevastating consequencesPregnancyEnvironmental Conditioning and Aerosol Infection of Mice.
Kudo E, Iwasaki A. Environmental Conditioning and Aerosol Infection of Mice. Bio-protocol 2020, 10: e3592. PMID: 33659558, PMCID: PMC7842367, DOI: 10.21769/bioprotoc.3592.Peer-Reviewed Original ResearchCutting 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 antibioticsMucosaInfectionSeasonality of Respiratory Viral Infections
Moriyama M, Hugentobler WJ, Iwasaki A. Seasonality of Respiratory Viral Infections. Annual Review Of Virology 2020, 7: 1-19. PMID: 32196426, DOI: 10.1146/annurev-virology-012420-022445.Peer-Reviewed Original ResearchMeSH KeywordsBetacoronavirusCoronavirus InfectionsCOVID-19HumansHumidityInfectious Disease Incubation PeriodInfluenza, HumanOrthomyxoviridaePandemicsPicornaviridae InfectionsPneumonia, ViralRespiratory Tract InfectionsRhinovirusSARS-CoV-2SeasonsSevere Acute Respiratory SyndromeSevere acute respiratory syndrome-related coronavirusSeverity of Illness IndexTemperatureConceptsRespiratory viral infectionsViral infectionSevere acute respiratory syndrome coronavirusAcute respiratory syndrome coronavirusViral respiratory infectionsAdaptive immune responsesRespiratory viral diseasesRespiratory infectionsRespiratory virusesInfluenza diseaseRespiratory tractImmune responseAnnual epidemicsHost responseInfectionMajor contributing factorViral diseasesDiseaseContributing factorVirus stabilityVirusEpidemicRecent studiesYearsHuman population