2024
Acute and persistent responses after H5N1 vaccination in humans
Apps R, Biancotto A, Candia J, Kotliarov Y, Perl S, Cheung F, Farmer R, Mulè M, Rachmaninoff N, Chen J, Martins A, Shi R, Zhou H, Bansal N, Schum P, Olnes M, Milanez-Almeida P, Han K, Sellers B, Cortese M, Hagan T, Rouphael N, Pulendran B, King L, Manischewitz J, Khurana S, Golding H, van der Most R, Dickler H, Germain R, Schwartzberg P, Tsang J. Acute and persistent responses after H5N1 vaccination in humans. Cell Reports 2024, 43: 114706. PMID: 39235945, DOI: 10.1016/j.celrep.2024.114706.Peer-Reviewed Original ResearchH5N1 influenza vaccineImpact vaccine responsesTime pointsAdjuvant AS03H5N1 vaccineInfluenza vaccineT cellsVaccine responseVaccinated cohortHigh antibody respondersImmune stateVaccine antigensMultiple time pointsSingle-cell profilingInitial vaccinationSystems immunologyVaccinePersistent responseSurface proteinsCell type-specific signaturesChromatin accessibilityTranscription factorsH5N1DaysAS03A unified metric of human immune health
Sparks R, Rachmaninoff N, Lau W, Hirsch D, Bansal N, Martins A, Chen J, Liu C, Cheung F, Failla L, Biancotto A, Fantoni G, Sellers B, Chawla D, Howe K, Mostaghimi D, Farmer R, Kotliarov Y, Calvo K, Palmer C, Daub J, Foruraghi L, Kreuzburg S, Treat J, Urban A, Jones A, Romeo T, Deuitch N, Moura N, Weinstein B, Moir S, Ferrucci L, Barron K, Aksentijevich I, Kleinstein S, Townsley D, Young N, Frischmeyer-Guerrerio P, Uzel G, Pinto-Patarroyo G, Cudrici C, Hoffmann P, Stone D, Ombrello A, Freeman A, Zerbe C, Kastner D, Holland S, Tsang J. A unified metric of human immune health. Nature Medicine 2024, 30: 2461-2472. PMID: 38961223, DOI: 10.1038/s41591-024-03092-6.Peer-Reviewed Original ResearchClinically healthy individualsHealthy individualsImmune cell frequenciesImmune healthInflammatory biomarkers C-reactive proteinC-reactive proteinBiomarkers C-reactive proteinResponse to immunizationAntibody response to immunizationInflammatory disease statesImmune pathologyDisease activityTreatment responseAntigenic stimulationImmune consequencesClinical dataImmunological pathwaysHealthy controlsCell frequencyInterleukin-6Nonimmunologic diseasesImmune diseasesMonogenic diseasesMonogenic conditionsMedication useIntegrating population and single-cell variations in vaccine responses identifies a naturally adjuvanted human immune setpoint
Mulè M, Martins A, Cheung F, Farmer R, Sellers B, Quiel J, Jain A, Kotliarov Y, Bansal N, Chen J, Schwartzberg P, Tsang J. Integrating population and single-cell variations in vaccine responses identifies a naturally adjuvanted human immune setpoint. Immunity 2024, 57: 1160-1176.e7. PMID: 38697118, DOI: 10.1016/j.immuni.2024.04.009.Peer-Reviewed Original ResearchConceptsTranscriptional statesVaccine responseSingle-cell profiling methodsSingle-cell variationAS03-adjuvanted vaccineUnadjuvanted influenza vaccineResponse to lipopolysaccharide stimulationB cell signaturesCD14<sup>+</sup> monocytesSingle-cell levelBiological insightsUnadjuvanted vaccineAS03-adjuvantedInfluenza vaccineResponse phenotypesCITE-seqInnate subsetsAdjuvant developmentHigh antibody respondersDay 1Antibody respondersLipopolysaccharide stimulationVaccineCorrelation networkHuman population
2023
Human transcriptional signature of protection after Plasmodium falciparum immunization and infectious challenge via mosquito bites
Mura M, Misganaw B, Gautam A, Robinson T, Chaudhury S, Bansal N, Martins A, Tsang J, Hammamieh R, Bergmann-Leitner E. Human transcriptional signature of protection after Plasmodium falciparum immunization and infectious challenge via mosquito bites. Human Vaccines & Immunotherapeutics 2023, 19: 2282693. PMID: 38010150, PMCID: PMC10760396, DOI: 10.1080/21645515.2023.2282693.Peer-Reviewed Original ResearchConceptsPeripheral blood mononuclear cellsNon-protected individualsHuman malaria infectionImmune correlatesMalaria infectionVaccine-induced responsesCorrelates of protectionTranscriptomic analysisBlood mononuclear cellsAntigen-specific stimulationTranscriptomic profilesAntigen-specific cellsWhole blood transcriptomic analysesImmune signaturesMalaria vaccineMononuclear cellsInfectious challengeVaccine platformEffective vaccineMosquito bitesLongitudinal time pointsSubunit vaccineInfectious pathogensTranscriptional eventsVaccineTracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine
de Assis F, Hoehn K, Zhang X, Kardava L, Smith C, Merhebi O, Buckner C, Trihemasava K, Wang W, Seamon C, Chen V, Schaughency P, Cheung F, Martins A, Chiang C, Li Y, Tsang J, Chun T, Kleinstein S, Moir S. Tracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine. Cell Reports 2023, 42: 112780. PMID: 37440409, PMCID: PMC10529190, DOI: 10.1016/j.celrep.2023.112780.Peer-Reviewed Original ResearchConceptsMemory B cellsB cell receptorB cellsAtypical memory B cellsInfection-naïve individualsTwo-dose SARSSARS-CoV-2 mRNAB cell responsesAntibody-secreting cellsMonth 6Protective immunityCell responsesCell receptorClonal expansionImmunoglobulin GEarly timepointsLater timepointsPlasmablastsVaccinationCD71TimepointsSurface proteinsCellsMultimodal single-cell analysisMRNAInfluenza vaccination reveals sex dimorphic imprints of prior mild COVID-19
Sparks R, Lau W, Liu C, Han K, Vrindten K, Sun G, Cox M, Andrews S, Bansal N, Failla L, Manischewitz J, Grubbs G, King L, Koroleva G, Leimenstoll S, Snow L, Chen J, Tang J, Mukherjee A, Sellers B, Apps R, McDermott A, Martins A, Bloch E, Golding H, Khurana S, Tsang J. Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19. Nature 2023, 614: 752-761. PMID: 36599369, PMCID: PMC10481789, DOI: 10.1038/s41586-022-05670-5.Peer-Reviewed Original ResearchConceptsMild COVID-19Control individualsInnate immune genesInfluenza vaccinationCOVID-19Day 28Day 1Viral infectionNon-hospitalized COVID-19Baseline immune statusAcute viral infectionSex-matched control individualsMemory-like CD8IL-15 responsesIL-15 stimulationSex-dimorphic effectsToll-like receptorsFuture immune responseHealthy control individualsImmune genesSystems immunology approachT-cell activation signaturesHealthy male individualsMale individualsMore IFNγ
2022
Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children
Xu Q, Milanez-Almeida P, Martins A, Radtke A, Hoehn K, Oguz C, Chen J, Liu C, Tang J, Grubbs G, Stein S, Ramelli S, Kabat J, Behzadpour H, Karkanitsa M, Spathies J, Kalish H, Kardava L, Kirby M, Cheung F, Preite S, Duncker P, Kitakule M, Romero N, Preciado D, Gitman L, Koroleva G, Smith G, Shaffer A, McBain I, McGuire P, Pittaluga S, Germain R, Apps R, Schwartz D, Sadtler K, Moir S, Chertow D, Kleinstein S, Khurana S, Tsang J, Mudd P, Schwartzberg P, Manthiram K. Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children. Nature Immunology 2022, 24: 186-199. PMID: 36536106, PMCID: PMC10777159, DOI: 10.1038/s41590-022-01367-z.Peer-Reviewed Original ResearchConceptsT cell receptorImmune responseGerminal centersPrevious SARS-CoV-2 infectionSARS-CoV-2 infectionB-cell receptor sequencingTissue-specific immunityCell receptor sequencingAdaptive immune responsesUpper respiratory tractMemory B cellsT cell clonotypesSite of infectionSARS-CoV-2Pharyngeal lymphoid tissuePeripheral bloodLymphocyte populationsLymphoid tissueRespiratory tractCell clonotypesAdaptive immunityB cellsCDR3 sequencesAdenoidsCell receptorNormalizing and denoising protein expression data from droplet-based single cell profiling
Mulè M, Martins A, Tsang J. Normalizing and denoising protein expression data from droplet-based single cell profiling. Nature Communications 2022, 13: 2099. PMID: 35440536, PMCID: PMC9018908, DOI: 10.1038/s41467-022-29356-8.Peer-Reviewed Original ResearchConceptsProtein expression dataSingle-cell profiling methodsExpression dataSingle-cell profilingOligo-conjugated antibodiesTechnical noiseProtein populationCITE-seqCellular heterogeneityComprehensive dissectionDownstream analysisCell profilingDSBsSingle cellsProtein levelsProtein expressionCell populationsOpen-source R packageProfiling methodProtein countsEmpty dropletsR packageComputational analysisCellsBiological variation
2021
Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential
Rogers D, Sood A, Wang H, van Beek J, Rademaker T, Artusa P, Schneider C, Shen C, Wong D, Bhagrath A, Lebel M, Condotta S, Richer M, Martins A, Tsang J, Barreiro L, François P, Langlais D, Melichar H, Textor J, Mandl J. Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential. Cell Reports 2021, 37: 110064. PMID: 34852223, DOI: 10.1016/j.celrep.2021.110064.Peer-Reviewed Original ResearchConceptsSingle-cell RNA sequencingGene expression differencesCell receptor signalingChromatin accessibilityLineage choiceTCR signal strengthCell chromatinTranscriptional differencesRNA sequencingExpression differencesReceptor signalingLandscape differencesEffector potentialEffector lineagesThymic developmentCellsNaive CD4Self-peptide MHCChromatinCognate antigenLineagesGenesSignalingTCR interactionsKey driversTime-resolved systems immunology reveals a late juncture linked to fatal COVID-19
Liu C, Martins AJ, Lau WW, Rachmaninoff N, Chen J, Imberti L, Mostaghimi D, Fink DL, Burbelo PD, Dobbs K, Delmonte OM, Bansal N, Failla L, Sottini A, Quiros-Roldan E, Lee Han K, Sellers BA, Cheung F, Sparks R, Chun TW, Moir S, Lionakis MS, , Rossi C, Su H, Kuhns D, Cohen J, Notarangelo L, Tsang J, , Abers M, Apps R, Bosticardo M, Milanez-Almeida P, Mulè M, Shaw E, Zhang Y, , Castelli F, Muiesan M, Tomasoni G, Scolari F, Tucci A. Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19. Cell 2021, 184: 1836-1857.e22. PMID: 33713619, PMCID: PMC7874909, DOI: 10.1016/j.cell.2021.02.018.Peer-Reviewed Original ResearchConceptsFatal COVID-19Peripheral immune cellsPlasmacytoid dendritic cellsPost-symptom onsetCOVID-19 patientsCOVID-19Fatty acid metabolismGene expression signaturesNK cellsSymptom onsetDendritic cellsSevere patientsFatal outcomeImmune response variationCellular inflammationImmune cellsInflammatory responseCell receptor sequencesExtensive patientClinical monitoringTherapeutic interventionsCell activationDay 17Disease severitySigns of exhaustion
2020
Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells
Baharom F, Ramirez-Valdez RA, Tobin KKS, Yamane H, Dutertre CA, Khalilnezhad A, Reynoso GV, Coble VL, Lynn GM, Mulè MP, Martins AJ, Finnigan JP, Zhang XM, Hamerman JA, Bhardwaj N, Tsang JS, Hickman HD, Ginhoux F, Ishizuka AS, Seder RA. Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells. Nature Immunology 2020, 22: 41-52. PMID: 33139915, PMCID: PMC7746638, DOI: 10.1038/s41590-020-00810-3.Peer-Reviewed Original ResearchConceptsNeoantigen-specific CD8T cellsToll-like receptor 7/8 agonistQuality of CD8Stem-like TCF1T cell immunityStem-like CD8Superior antitumor responsesPersonalized cancer vaccinesStem-like genesStem-like cellsIntravenous vaccinationNanoparticle vaccinationAntitumor immunityCheckpoint blockadeCell immunityDendritic cellsAntitumor responseEffector cellsSubcutaneous immunizationCancer vaccinesVaccine parametersNeoantigen peptidesAntigen presentationNanoparticle vaccineBroad immune activation underlies shared set point signatures for vaccine responsiveness in healthy individuals and disease activity in patients with lupus
Kotliarov Y, Sparks R, Martins A, Mulè M, Lu Y, Goswami M, Kardava L, Banchereau R, Pascual V, Biancotto A, Chen J, Schwartzberg P, Bansal N, Liu C, Cheung F, Moir S, Tsang J. Broad immune activation underlies shared set point signatures for vaccine responsiveness in healthy individuals and disease activity in patients with lupus. Nature Medicine 2020, 26: 618-629. PMID: 32094927, PMCID: PMC8392163, DOI: 10.1038/s41591-020-0769-8.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAdolescentAdultAgedAged, 80 and overAntibody FormationB-LymphocytesChildChild, PreschoolCohort StudiesFemaleGene Expression ProfilingHumansInfluenza VaccinesInfluenza, HumanLupus Erythematosus, SystemicMaleMiddle AgedTranscriptomeVaccinationYellow FeverYellow Fever VaccineYoung AdultConceptsDisease activityVaccine responsivenessAutoimmune disease activityBlood transcriptional signaturesYellow fever vaccinationSystemic lupus erythematosusClinical quiescenceFever vaccinationLupus erythematosusCancer immunotherapyBaseline predictorsDisease outcomeHealthy subjectsImmune responseI IFNHealthy individualsVaccinationTranscriptional signatureImmune variationBaseline statePatientsExtent of activationBiological basisSurface proteinsInfection responseCancer prognosis with shallow tumor RNA sequencing
Milanez-Almeida P, Martins A, Germain R, Tsang J. Cancer prognosis with shallow tumor RNA sequencing. Nature Medicine 2020, 26: 188-192. PMID: 32042193, DOI: 10.1038/s41591-019-0729-3.Peer-Reviewed Original ResearchConceptsCancer prognosisTumor RNA-seq dataTumor RNA sequencingPrediction of outcomeTypes of cancerClinical outcomesRNA sequencingAdverse outcomesRelative riskDisease outcomeOutcome predictionTumor RNA-seqPersonalized oncologyTranscriptional signatureCancer1–3Molecular pathwaysOutcomesPrognosisLongitudinal analysisTranscriptional pathwaysCancer
2019
Differential Expression of the Transcription Factor GATA3 Specifies Lineage and Functions of Innate Lymphoid Cells
Zhong C, Zheng M, Cui K, Martins A, Hu G, Li D, Tessarollo L, Kozlov S, Keller J, Tsang J, Zhao K, Zhu J. Differential Expression of the Transcription Factor GATA3 Specifies Lineage and Functions of Innate Lymphoid Cells. Immunity 2019, 52: 83-95.e4. PMID: 31882362, PMCID: PMC6962539, DOI: 10.1016/j.immuni.2019.12.001.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineageCells, CulturedGATA3 Transcription FactorInhibitor of Differentiation Protein 2Interleukin Receptor Common gamma SubunitMiceMice, Inbred C57BLMice, KnockoutNuclear Receptor Subfamily 1, Group F, Member 3Programmed Cell Death 1 ReceptorPromyelocytic Leukemia Zinc Finger ProteinStem CellsT-Lymphocyte SubsetsT-Lymphocytes, Helper-InducerConceptsILC progenitorsDifferential expressionTranscription factor PLZFTranscriptional regulator Id2Common progenitorLymphoid progenitorsGATA3 expressionConditional deletionProgenitorsPLZFInnate lymphoid cellsExpressionLymphoid tissue inducer cellsLymphoid cellsLTi cellsCellsGATA3FateTranscription factor RORγtILC subsetsLineagesTranscriptionId2DeletionHigh amountsOverexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation
Austin JW, Buckner CM, Kardava L, Wang W, Zhang X, Melson VA, Swanson RG, Martins AJ, Zhou JQ, Hoehn KB, Fisk JN, Dimopoulos Y, Chassiakos A, O'Dell S, Smelkinson MG, Seamon CA, Kwan RW, Sneller MC, Pittaluga S, Doria-Rose NA, McDermott A, Li Y, Chun TW, Kleinstein SH, Tsang JS, Petrovas C, Moir S. Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation. Science Translational Medicine 2019, 11 PMID: 31776286, PMCID: PMC7479651, DOI: 10.1126/scitranslmed.aax0904.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntibodies, NeutralizingAntibody AffinityAntigens, CD19B-LymphocytesCytokinesFemaleGerminal CenterHIV InfectionsHumansImmunologic MemoryLymph NodesMaleMiddle AgedMutation RatePhenotypeReceptors, Antigen, B-CellT-Box Domain ProteinsT-Lymphocytes, Helper-InducerTranscriptomeYoung AdultConceptsHIV-specific B cellsT-betGC B cellsGerminal centersB cellsLymph nodesPoor affinity maturationChronic immune activationMemory B cell compartmentAntibody-mediated immunityChronic infectious diseaseOptimal antibody responseB cell compartmentChronic human infectionsB cell receptorHIV viremiaImmunologic outcomesHIV infectionViremic individualsChronic viremiaImmune activationPeripheral bloodProtective antibodiesAntibody responseCD19IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses
Gottschalk R, Dorrington M, Dutta B, Krauss K, Martins A, Uderhardt S, Chan W, Tsang J, Torabi-Parizi P, Fraser I, Germain R. IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses. ELife 2019, 8: e46836. PMID: 31385572, PMCID: PMC6684266, DOI: 10.7554/elife.46836.Peer-Reviewed Original ResearchConceptsContext-dependent regulationGram-positive speciesGram-negative bacteriaClass-specific mannerInflammatory responseRegulatory eventsMolecular mechanismsMacrophage inflammatory responseMouse macrophagesLigand pairsInnate immunityInflammatory cytokine productionMacrophage responseBacteriaRegulationSpecific pathogensIL-10Cytokine productionLung infectionProduction dynamicsInhibitory eventsSpeciesMacrophagesNegative feedbackInflammation dynamicsResident Macrophages Cloak Tissue Microlesions to Prevent Neutrophil-Driven Inflammatory Damage
Uderhardt S, Martins A, Tsang J, Lämmermann T, Germain R. Resident Macrophages Cloak Tissue Microlesions to Prevent Neutrophil-Driven Inflammatory Damage. Cell 2019, 177: 541-555.e17. PMID: 30955887, PMCID: PMC6474841, DOI: 10.1016/j.cell.2019.02.028.Peer-Reviewed Original ResearchConceptsTissue-resident macrophagesTissue homeostasisDiverse tissuesCell deathOrgan architectureIndividual cellsNeutrophil swarmsResident macrophagesDense swarmsLocal cell injuryIntravital imagingLocal disruptionParenchymal cell deathDynamic intravital imagingInescapable consequenceCell damageCell injuryHomeostasisMacrophagesCascadeInflammatory damageDamageCellsAccumulationDisruption
2018
Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism
Mao K, Baptista A, Tamoutounour S, Zhuang L, Bouladoux N, Martins A, Huang Y, Gerner M, Belkaid Y, Germain R. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 2018, 554: 255-259. PMID: 29364878, DOI: 10.1038/nature25437.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAnimalsCD4-Positive T-LymphocytesEpithelial CellsGastrointestinal MicrobiomeHomeodomain ProteinsHomeostasisImmunity, InnateInflammationInterleukin-23InterleukinsIntestine, SmallLipid MetabolismLymphocyte ActivationLymphocytesMaleMiceMonocytesPhosphorylationReceptors, CCR2STAT3 Transcription FactorSymbiosisTh17 CellsT-Lymphocytes, RegulatoryWeaning
2017
Transcriptional Response of Respiratory Epithelium to Nontuberculous Mycobacteria
Matsuyama M, Martins A, Shallom S, Kamenyeva O, Kashyap A, Sampaio E, Kabat J, Olivier K, Zelazny A, Tsang J, Holland S. Transcriptional Response of Respiratory Epithelium to Nontuberculous Mycobacteria. American Journal Of Respiratory Cell And Molecular Biology 2017, 58: 241-252. PMID: 28915071, PMCID: PMC5806000, DOI: 10.1165/rcmb.2017-0218oc.Peer-Reviewed Original ResearchConceptsCholesterol biosynthesisUpregulation of genesRespiratory epitheliumGene expression signaturesCiliary genesTranscriptional responseRNA sequencingEpithelial cell infectionResponse genesInflammatory response genesHost responseCytokine/chemokine productionRespiratory epithelial cell culturesEpithelial cell culturesPulmonary nontuberculous mycobacteria (NTM) diseaseExpression signaturesMajor host responsesCytokines/chemokinesGenesRespiratory epithelial cellsCiliary functionNontuberculous mycobacteria diseaseCell infectionMultiplicity of infectionBiosynthesisEnvironment Tunes Propagation of Cell-to-Cell Variation in the Human Macrophage Gene Network
Martins A, Narayanan M, Prüstel T, Fixsen B, Park K, Gottschalk R, Lu Y, Andrews-Pfannkoch C, Lau W, Wendelsdorf K, Tsang J. Environment Tunes Propagation of Cell-to-Cell Variation in the Human Macrophage Gene Network. Cell Systems 2017, 4: 379-392.e12. PMID: 28365150, PMCID: PMC8392141, DOI: 10.1016/j.cels.2017.03.002.Peer-Reviewed Original ResearchConceptsGene networksCellular adaptationCell variationSingle-cell transcriptomic studiesGene-gene correlationsUnderlying regulatory mechanismsDegree of phosphorylationPhenotypic diversityTranscriptomic studiesEnvironmental adaptationMultiple molecular parametersGene expressionRegulatory mechanismsCellular heterogeneityDistinct environmentsSingle cellsHuman macrophagesQuantitative tuningCell populationsNatural perturbationsGenesDifferent environmentsSuch variationCellsStochastic simulation analysis