2024
Integrating 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 receptor
2021
Time-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
Broad 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
Overexpression 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 responseCD19
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
2016
Robust Inference of Cell-to-Cell Expression Variations from Single- and K-Cell Profiling
Narayanan M, Martins A, Tsang J. Robust Inference of Cell-to-Cell Expression Variations from Single- and K-Cell Profiling. PLOS Computational Biology 2016, 12: e1005016. PMID: 27438699, PMCID: PMC4954693, DOI: 10.1371/journal.pcbi.1005016.Peer-Reviewed Original ResearchConceptsSingle-cell expression levelsExpression levelsNovel biological informationSingle cellsKey inflammatory genesExpression variationGene expressionCellular heterogeneityBiological informationRandom poolSingle populationHuman macrophagesBiological conditionsCell populationsGenesMultiplexed technologiesK cellsInflammatory genesCellsBiological varianceQuantifying differencesSensitive technologyContinuous variationRobust inferenceProfilingDistinct NF-κB and MAPK Activation Thresholds Uncouple Steady-State Microbe Sensing from Anti-pathogen Inflammatory Responses
Gottschalk R, Martins A, Angermann B, Dutta B, Ng C, Uderhardt S, Tsang J, Fraser I, Meier-Schellersheim M, Germain R. Distinct NF-κB and MAPK Activation Thresholds Uncouple Steady-State Microbe Sensing from Anti-pathogen Inflammatory Responses. Cell Systems 2016, 2: 378-390. PMID: 27237739, PMCID: PMC4919147, DOI: 10.1016/j.cels.2016.04.016.Peer-Reviewed Original ResearchConceptsNF-κBMAPK activationInflammatory mediator productionSet of genesInnate immune response systemNF-κB signalingInnate immune systemSwitch-like mannerMacrophage functional responsesImmune response systemInflammatory mediatorsTLR4 ligandMediator productionInflammatory responseMicrobial stimuliInnate responseImmune systemMAPK signalingMacrophage primingLigand sensitivityHuman macrophagesInverse correlationInvasive pathogensSingle receptorGenes
2014
Random yet deterministic: convergent immunoglobulin responses to influenza
Martins A, Tsang J. Random yet deterministic: convergent immunoglobulin responses to influenza. Trends In Microbiology 2014, 22: 488-489. PMID: 25179798, PMCID: PMC4961090, DOI: 10.1016/j.tim.2014.07.005.Commentaries, Editorials and Letters
2012
Recent progress using systems biology approaches to better understand molecular mechanisms of immunity
Gottschalk R, Martins A, Sjoelund V, Angermann B, Lin B, Germain R. Recent progress using systems biology approaches to better understand molecular mechanisms of immunity. Seminars In Immunology 2012, 25: 201-208. PMID: 23238271, PMCID: PMC3834012, DOI: 10.1016/j.smim.2012.11.002.Commentaries, Editorials and LettersConceptsSystems biology approachBiology approachSingle-cell measurement technologiesTranscriptional networksSpatial regulationHigh-throughput data acquisitionMolecular mechanismsComputational integrationImmune systemFeedback loopNovel perturbationRecent progressSignalingReductionist researchRegulationBroad rangePotential sourceFunctionResponse heterogeneity
2010
Lactobacillus rhamnosus GR-1-Induced IL-10 Production in Human Placental Trophoblast Cells Involves Activation of JAK/STAT and MAPK Pathways
Yeganegi M, Leung C, Martins A, Kim S, Reid G, Challis J, Bocking A. Lactobacillus rhamnosus GR-1-Induced IL-10 Production in Human Placental Trophoblast Cells Involves Activation of JAK/STAT and MAPK Pathways. Reproductive Sciences 2010, 17: 1043-1051. PMID: 20858906, DOI: 10.1177/1933719110377237.Peer-Reviewed Original ResearchConceptsHuman placental trophoblast cellsPlacental trophoblast cellsPreterm birthEnzyme-linked immunosorbent assayRhamnosus GR-1Gr-1Trophoblast cellsIntrauterine infection/inflammationAnti-inflammatory effectsIL-10 productionInfection/inflammationWestern blot analysisHealthy pregnancyPhosphorylation of STAT3IL-10Janus kinase/signal transducerJAK/STATCytokine regulationKinase/signal transducerPotential preventionPlacental trophoblastsMitogen-activated protein kinase pathwayAbsence of pretreatmentHuman placentaSTAT-3Lactobacillus rhamnosus GR-1 Stimulates Colony-Stimulating Factor 3 (Granulocyte) (CSF3) Output in Placental Trophoblast Cells in a Fetal Sex-Dependent Manner1
Yeganegi M, Leung C, Martins A, Kim S, Reid G, Challis J, Bocking A. Lactobacillus rhamnosus GR-1 Stimulates Colony-Stimulating Factor 3 (Granulocyte) (CSF3) Output in Placental Trophoblast Cells in a Fetal Sex-Dependent Manner1. Biology Of Reproduction 2010, 84: 18-25. PMID: 20811016, PMCID: PMC4480822, DOI: 10.1095/biolreprod.110.085167.Peer-Reviewed Original ResearchConceptsPlacental trophoblast cellsTrophoblast cellsPreterm birthFetal sex-dependent mannerAnti-inflammatory effectsJanus kinaseSex-dependent mannerColony-stimulating factor 3Mitogen-activated protein kinase 14Western blot analysisPreterm laborPhosphorylation of STAT3Interleukin-10Bacterial vaginosisTherapeutic benefitFemale fetusesProtein kinase 14Placenta culturesAbsence of pretreatmentMAPK14 inhibitorSignal transducerTranscription 3Cell preparationsUnderlying mechanismBlot analysisThe multifaceted effects of granulocyte colony‐stimulating factor in immunomodulation and potential roles in intestinal immune homeostasis
Martins A, Han J, Kim S. The multifaceted effects of granulocyte colony‐stimulating factor in immunomodulation and potential roles in intestinal immune homeostasis. IUBMB Life 2010, 62: 611-617. PMID: 20681025, PMCID: PMC2916186, DOI: 10.1002/iub.361.Commentaries, Editorials and LettersConceptsColony-stimulating factorIntestinal immune homeostasisGranulocyte colony-stimulating factorImmune homeostasisMacrophage colony-stimulating factorG-CSFLocal immune homeostasisEndogenous G-CSFPotential roleMonocytes/macrophagesExogenous G-CSFGranulocyte/macrophage colony-stimulating factorDendritic cellsImmunosuppressive effectsImmunomodulatory effectsImmune cellsT lymphocytesImmune functionGM-CSFMyeloid hematopoiesisM-CSFImmunomodulationHomeostasisCellsFactors
2009
Effect of Lactobacillus rhamnosus GR-1 supernatant and fetal sex on lipopolysaccharide-induced cytokine and prostaglandin-regulating enzymes in human placental trophoblast cells: implications for treatment of bacterial vaginosis and prevention of preterm labor
Yeganegi M, Watson C, Martins A, Kim S, Reid G, Challis J, Bocking A. Effect of Lactobacillus rhamnosus GR-1 supernatant and fetal sex on lipopolysaccharide-induced cytokine and prostaglandin-regulating enzymes in human placental trophoblast cells: implications for treatment of bacterial vaginosis and prevention of preterm labor. American Journal Of Obstetrics And Gynecology 2009, 200: 532.e1-532.e8. PMID: 19285652, DOI: 10.1016/j.ajog.2008.12.032.Peer-Reviewed Original ResearchMeSH KeywordsCells, CulturedCyclooxygenase 2CytokinesFemaleHumansHydroxyprostaglandin DehydrogenasesInterleukin-10Interleukin-1betaLacticaseibacillus rhamnosusLipopolysaccharidesMaleObstetric Labor, PrematurePregnancyProbioticsSex FactorsToll-Like Receptor 4TrophoblastsTumor Necrosis Factor-alphaVaginosis, BacterialConceptsToll-like receptor 4Prostaglandin-endoperoxide synthase 2Placental trophoblast cellsIL-10Prostaglandin dehydrogenaseTrophoblast cellsPreterm laborTNF-alphaMale placentasFetal sexOutput of cytokinesHuman placental trophoblast cellsTumor necrosis factorEffects of lipopolysaccharideLipopolysaccharide-induced cytokineEnzyme-linked immunosorbentStudent's t-testPreterm birthBacterial vaginosisIL-1betaReceptor 4Necrosis factorTherapeutic benefitFemale placentasMale fetuses
2008
Reduced Expression of Basal and Probiotic-inducible G-CSF in Intestinal Mononuclear Cells Is Associated with Inflammatory Bowel Disease
Martins A, Colquhoun P, Reid G, Kim S. Reduced Expression of Basal and Probiotic-inducible G-CSF in Intestinal Mononuclear Cells Is Associated with Inflammatory Bowel Disease. Inflammatory Bowel Diseases 2008, 15: 515-525. PMID: 19058228, DOI: 10.1002/ibd.20808.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEscherichia coliGranulocyte Colony-Stimulating FactorHumansInflammatory Bowel DiseasesInterleukin-12Interleukin-23Intestinal MucosaLacticaseibacillus rhamnosusLeukocytes, MononuclearMiceMice, Inbred C57BLMucous MembraneProbioticsReceptors, Granulocyte Colony-Stimulating FactorTumor Necrosis Factor-alphaConceptsGranulocyte-colony stimulating factorInflammatory bowel diseaseHuman peripheral blood mononuclear cellsPeripheral blood mononuclear cellsG-CSF productionIntestinal mononuclear cellsBlood mononuclear cellsMononuclear cellsRhamnosus GR-1L. rhamnosus GR-1IL-23Bowel diseaseIntestinal lamina propria mononuclear cellsGr-1Intestinal lamina propria cellsLamina propria mononuclear cellsNon-IBD patientsReceptor knockout miceReceptor-deficient miceProinflammatory cytokine productionLamina propria cellsBone marrow-derived macrophagesIntestinal tissue samplesMarrow-derived macrophagesG-CSF release