Featured Publications
PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
Xu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 2023, 619: 819-827. PMID: 37438530, PMCID: PMC10371867, DOI: 10.1038/s41586-023-06322-y.Peer-Reviewed Original ResearchConceptsC-terminal β-barrel domainSpike-mediated fusionCell-autonomous defenseLarge-scale exome sequencingΒ-barrel domainGenome-wide CRISPRSARS-CoV-2 infectionHost cell cytosolScramblase activityPhospholipid scramblaseLive SARS-CoV-2 infectionHuman lung epitheliumPLSCR1SARS-CoV-2 USASingle-molecule switchingSARS-CoV-2 variantsExome sequencingHuman populationRestriction factorsViral RNANew SARS-CoV-2 variantsSARS-CoV-2Robust activityLung epitheliumDefense factorsA statistical framework to identify cell types whose genetically regulated proportions are associated with complex diseases
Liu W, Deng W, Chen M, Dong Z, Zhu B, Yu Z, Tang D, Sauler M, Lin C, Wain L, Cho M, Kaminski N, Zhao H. A statistical framework to identify cell types whose genetically regulated proportions are associated with complex diseases. PLOS Genetics 2023, 19: e1010825. PMID: 37523391, PMCID: PMC10414598, DOI: 10.1371/journal.pgen.1010825.Peer-Reviewed Original ResearchConceptsCell typesDisease-associated tissuesWide association studyComplex diseasesCell type proportionsDisease-relevant tissuesReal GWAS dataFunctional genesTranscriptomic dataGWAS dataGenetic dataAssociation studiesNovel statistical frameworkChronic obstructive pulmonary diseaseStatistical frameworkObstructive pulmonary diseaseIdiopathic pulmonary fibrosisBreast cancer riskType proportionsBlood CD8Pulmonary diseasePulmonary fibrosisPredictive biomarkersLung tissueBreast cancerVISTA (PD-1H) Is a Crucial Immune Regulator to Limit Pulmonary Fibrosis.
Kim S, Adams T, Hu Q, Shin H, Chae G, Lee S, Sharma L, Kwon H, Lee F, Park H, Huh W, Manning E, Kaminski N, Sauler M, Chen L, Song J, Kim T, Kang M. VISTA (PD-1H) Is a Crucial Immune Regulator to Limit Pulmonary Fibrosis. American Journal Of Respiratory Cell And Molecular Biology 2023, 69: 22-33. PMID: 36450109, PMCID: PMC10324045, DOI: 10.1165/rcmb.2022-0219oc.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisPulmonary fibrosisImmune regulatorsTherapeutic potentialHuman idiopathic pulmonary fibrosisCrucial immune regulatorsNovel immune regulatorPulmonary fibrosis micePulmonary fibrosis modelNovel therapeutic targetRole of VISTAWild-type littermatesMonocyte-derived macrophagesT lymphocyte lineageVISTA expressionIPF treatmentAntibody treatmentImmune landscapeFibrotic mediatorsLung fibrosisFibrosis miceInflammatory responseFibrosis modelMyeloid populationsTherapeutic targetBlood transcriptional correlates of BCG-induced protection against tuberculosis in rhesus macaques
Liu Y, Darrah P, Zeppa J, Kamath M, Laboune F, Douek D, Maiello P, Roederer M, Flynn J, Seder R, Khatri P. Blood transcriptional correlates of BCG-induced protection against tuberculosis in rhesus macaques. Cell Reports Medicine 2023, 4: 101096. PMID: 37390827, PMCID: PMC10394165, DOI: 10.1016/j.xcrm.2023.101096.Peer-Reviewed Original ResearchConceptsArea under the receiver operating characteristic curveDay 2 post-vaccinationCorrelates of vaccine-induced protectionRobust correlates of protectionLow-dose recipientsHigh-dose i.Rhesus macaquesBCG-induced protectionCorrelates of protectionResponse to i.Receiver operating characteristic curveType 1 interferonVaccine-induced protectionBCG recipientsCohort of macaquesCD4 TPeripheral bloodWeek 8Receptor signaling pathwayTuberculosisCharacteristic curveBCGBlood transcriptomeMycobacterium tuberculosisBloodA lung targeted miR-29 mimic as a therapy for pulmonary fibrosis
Chioccioli M, Roy S, Newell R, Pestano L, Dickinson B, Rigby K, Herazo-Maya J, Jenkins G, Ian S, Saini G, Johnson SR, Braybrooke R, Yu G, Sauler M, Ahangari F, Ding S, DeIuliis J, Aurelien N, Montgomery RL, Kaminski N. A lung targeted miR-29 mimic as a therapy for pulmonary fibrosis. EBioMedicine 2022, 85: 104304. PMID: 36265417, PMCID: PMC9587275, DOI: 10.1016/j.ebiom.2022.104304.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisNon-human primatesPulmonary fibrosisAnimal modelsPro-fibrotic genesAnti-fibrotic efficacyMiR-29 mimicsHuman peripheral bloodMiR-29b levelsHuman lung fibroblastsIPF patientsIPF diagnosisPeripheral bloodReduced fibrosisAdverse findingsPotential therapyLung slicesTGF-β1Relevant dosesLung fibroblastsNIH-NHLBIFibrosisTherapyCollagen productionProfibrotic gene programAPOBEC mutagenesis and selection for NFE2L2 contribute to the origin of lung squamous-cell carcinoma
Cannataro VL, Kudalkar S, Dasari K, Gaffney SG, Lazowski HM, Jackson LK, Yildiz I, Das RK, Rothberg BE, Anderson KS, Townsend JP. APOBEC mutagenesis and selection for NFE2L2 contribute to the origin of lung squamous-cell carcinoma. Lung Cancer 2022, 171: 34-41. PMID: 35872531, PMCID: PMC10126952, DOI: 10.1016/j.lungcan.2022.07.004.Peer-Reviewed Original ResearchConceptsCytidine deaminationMutagenic processesDefective homologous recombinationGenomic sequencesHomologous recombinationAttractive potential targetAPOBEC mutagenesisLung squamous cell carcinomaDeamination activityCancer cell growthAPOBEC proteinsAPOBEC activityCell growthCellular proliferationNFE2L2MutationsMolecular investigationsCancer effectsPotential targetMolecular variantsAPOBECSurvival of cancerSquamous cell carcinomaDeaminationVariantsCharacterization of the COPD alveolar niche using single-cell RNA sequencing
Sauler M, McDonough JE, Adams TS, Kothapalli N, Barnthaler T, Werder RB, Schupp JC, Nouws J, Robertson MJ, Coarfa C, Yang T, Chioccioli M, Omote N, Cosme C, Poli S, Ayaub EA, Chu SG, Jensen KH, Gomez JL, Britto CJ, Raredon MSB, Niklason LE, Wilson AA, Timshel PN, Kaminski N, Rosas IO. Characterization of the COPD alveolar niche using single-cell RNA sequencing. Nature Communications 2022, 13: 494. PMID: 35078977, PMCID: PMC8789871, DOI: 10.1038/s41467-022-28062-9.Peer-Reviewed Original ResearchConceptsSingle-cell RNA sequencingRNA sequencingCell-specific mechanismsChronic obstructive pulmonary diseaseAdvanced chronic obstructive pulmonary diseaseTranscriptomic network analysisSingle-cell RNA sequencing profilesCellular stress toleranceAberrant cellular metabolismStress toleranceRNA sequencing profilesTranscriptional evidenceCellular metabolismAlveolar nicheSequencing profilesHuman alveolar epithelial cellsChemokine signalingAlveolar epithelial type II cellsObstructive pulmonary diseaseSitu hybridizationType II cellsEpithelial type II cellsSequencingCOPD pathobiologyHuman lung tissue samplesLive imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy
Ullah I, Prévost J, Ladinsky MS, Stone H, Lu M, Anand SP, Beaudoin-Bussières G, Symmes K, Benlarbi M, Ding S, Gasser R, Fink C, Chen Y, Tauzin A, Goyette G, Bourassa C, Medjahed H, Mack M, Chung K, Wilen CB, Dekaban GA, Dikeakos JD, Bruce EA, Kaufmann DE, Stamatatos L, McGuire AT, Richard J, Pazgier M, Bjorkman PJ, Mothes W, Finzi A, Kumar P, Uchil PD. Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy. Immunity 2021, 54: 2143-2158.e15. PMID: 34453881, PMCID: PMC8372518, DOI: 10.1016/j.immuni.2021.08.015.Peer-Reviewed Original ResearchConceptsCOVID-19 convalescent subjectsSARS-CoV-2 infectionBioluminescence imagingK18-hACE2 miceLive bioluminescence imagingNatural killer cellsFc effector functionsSARS-CoV-2Convalescent subjectsKiller cellsPotent NAbsImmune protectionInflammatory responseEffector functionsNasal cavityNaB treatmentOptimal efficacyFc functionDepletion studiesMiceNAbsCOVID-19Direct neutralizationInfectionAntibodiesIntegrated Single-Cell Atlas of Endothelial Cells of the Human Lung
Schupp JC, Adams TS, Cosme C, Raredon MSB, Yuan Y, Omote N, Poli S, Chioccioli M, Rose KA, Manning EP, Sauler M, DeIuliis G, Ahangari F, Neumark N, Habermann AC, Gutierrez AJ, Bui LT, Lafyatis R, Pierce RW, Meyer KB, Nawijn MC, Teichmann SA, Banovich NE, Kropski JA, Niklason LE, Pe’er D, Yan X, Homer RJ, Rosas IO, Kaminski N. Integrated Single-Cell Atlas of Endothelial Cells of the Human Lung. Circulation 2021, 144: 286-302. PMID: 34030460, PMCID: PMC8300155, DOI: 10.1161/circulationaha.120.052318.Peer-Reviewed Original ResearchConceptsDifferential expression analysisPrimary lung endothelial cellsLung endothelial cellsCell typesMarker genesExpression analysisSingle-cell RNA sequencing dataCross-species analysisVenous endothelial cellsEndothelial marker genesSingle-cell atlasMarker gene setsRNA sequencing dataEndothelial cellsSubsequent differential expression analysisDifferent lung cell typesResident cell typesLung cell typesCellular diversityEndothelial cell typesCapillary endothelial cellsHuman lung endothelial cellsPhenotypic diversityEndothelial diversityIndistinguishable populationsSPLUNC1: a novel marker of cystic fibrosis exacerbations
Khanal S, Webster M, Niu N, Zielonka J, Nunez M, Chupp G, Slade MD, Cohn L, Sauler M, Gomez JL, Tarran R, Sharma L, Dela Cruz CS, Egan M, Laguna T, Britto CJ. SPLUNC1: a novel marker of cystic fibrosis exacerbations. European Respiratory Journal 2021, 58: 2000507. PMID: 33958427, PMCID: PMC8571118, DOI: 10.1183/13993003.00507-2020.Peer-Reviewed Original ResearchConceptsAcute pulmonary exacerbationsSPLUNC1 levelsCystic fibrosisClinical outcomesCF participantsLong-term disease controlNasal epithelium clone 1Cystic fibrosis exacerbationsHigher AE riskLung function declineCytokines interleukin-1βTumor necrosis factorAE riskClinical worseningPulmonary exacerbationsStable patientsLung functionAirway clearanceFunction declineSputum collectionAcute inflammationInflammatory cytokinesMicrobiology findingsCF careClinical managementElevated IL-15 concentrations in the sarcoidosis lung are independent of granuloma burden and disease phenotypes
Minasyan M, Sharma L, Pivarnik T, Liu W, Adams T, Bermejo S, Peng X, Liu A, Ishikawa G, Perry C, Kaminski N, Gulati M, Herzog EL, Dela Cruz CS, Ryu C. Elevated IL-15 concentrations in the sarcoidosis lung are independent of granuloma burden and disease phenotypes. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2021, 320: l1137-l1146. PMID: 33851886, PMCID: PMC8285626, DOI: 10.1152/ajplung.00575.2020.Peer-Reviewed Original ResearchConceptsIL-15 concentrationsIL-15Bronchoalveolar lavageDisease pathogenesisSarcoidosis lungClinical manifestationsLineages of miceIL-15 receptor αHuman cohortsInflammation of sarcoidosisIL-15 levelsOngoing inflammatory processSystemic granulomatous diseaseNumber of granulomasDisease phenotypeSarcoidosis cohortTDM administrationGranuloma numberComorbid conditionsClinical progressionInterleukin-15Granulomatous diseaseInflammatory processGranuloma formationHealthy controlsMicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease
Nouws J, Wan F, Finnemore E, Roque W, Kim SJ, Bazan IS, Li CX, Sköld C, Dai Q, Yan X, Chioccioli M, Neumeister V, Britto CJ, Sweasy J, Bindra RS, Wheelock ÅM, Gomez JL, Kaminski N, Lee PJ, Sauler M. MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease. JCI Insight 2021, 6: e134218. PMID: 33290275, PMCID: PMC7934877, DOI: 10.1172/jci.insight.134218.Peer-Reviewed Original ResearchConceptsCellular stress responseStress responseHomology-directed DNA repairDNA damage responseProtein BRCA1Damage responseCellular stressDNA repairProtein BimCOPD lung tissueLung epithelial cellsCellular responsesExpression arraysEpithelial cell apoptosisDNA damageChronic obstructive pulmonary diseaseBRCA1 expressionCell apoptosisApoptosisEpithelial cellsCritical mechanismMicroRNAsRegulatorObstructive pulmonary diseaseIncreases SusceptibilityCo-option of Neutrophil Fates by Tissue Environments
Ballesteros I, Rubio-Ponce A, Genua M, Lusito E, Kwok I, Fernández-Calvo G, Khoyratty TE, van Grinsven E, González-Hernández S, Nicolás-Ávila JÁ, Vicanolo T, Maccataio A, Benguría A, Li JL, Adrover JM, Aroca-Crevillen A, Quintana JA, Martín-Salamanca S, Mayo F, Ascher S, Barbiera G, Soehnlein O, Gunzer M, Ginhoux F, Sánchez-Cabo F, Nistal-Villán E, Schulz C, Dopazo A, Reinhardt C, Udalova IA, Ng LG, Ostuni R, Hidalgo A. Co-option of Neutrophil Fates by Tissue Environments. Cell 2020, 183: 1282-1297.e18. PMID: 33098771, DOI: 10.1016/j.cell.2020.10.003.Peer-Reviewed Original ResearchConceptsNeutrophil fateDepletion of neutrophilsHematopoietic recoveryVascular repairNeutrophil statesNeutrophil propertiesViral infectionNeutrophilsTarget tissuesHealthy tissueGenotoxic injuryEarly ageMultiple tissuesTissueTissue environmentPhysiological demandsInflammationHematopoietic homeostasisCXCR4LungNon-canonical functionsInjuryCancerInfectionLeukocytesQuantification of bronchoalveolar neutrophil extracellular traps and phagocytosis in murine pneumonia
Gautam S, Stahl Y, Young GM, Howell R, Cohen AJ, Tsang DA, Martin T, Sharma L, Dela Cruz CS. Quantification of bronchoalveolar neutrophil extracellular traps and phagocytosis in murine pneumonia. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2020, 319: l661-l669. PMID: 32783617, PMCID: PMC7642899, DOI: 10.1152/ajplung.00316.2020.Peer-Reviewed Original ResearchConceptsNeutrophil extracellular trapsAcute respiratory distress syndromeChronic obstructive pulmonary diseaseNeutrophil responseExtracellular trapsDysregulation of neutrophilsObstructive pulmonary diseaseRespiratory distress syndromeNeutrophil effector functionsEx vivo assaysBronchoalveolar neutrophilsSevere asthmaDistress syndromeLung neutrophilsPulmonary diseaseMurine pneumoniaMurine modelEffector functionsNeutrophil researchMouse lungCystic fibrosisMethodologic issuesMurine researchLungArray of diseasesSingle-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis
Adams TS, Schupp JC, Poli S, Ayaub EA, Neumark N, Ahangari F, Chu SG, Raby BA, DeIuliis G, Januszyk M, Duan Q, Arnett HA, Siddiqui A, Washko GR, Homer R, Yan X, Rosas IO, Kaminski N. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Science Advances 2020, 6: eaba1983. PMID: 32832599, PMCID: PMC7439502, DOI: 10.1126/sciadv.aba1983.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisVascular endothelial cellsIPF lungsPulmonary fibrosisChronic obstructive pulmonary disease (COPD) lungsFatal interstitial lung diseaseEndothelial cellsInterstitial lung diseaseCell populationsIPF myofibroblastsMyofibroblast fociNonsmoker controlsLung diseaseCOPD lungsBasaloid cellsSingle-cell atlasInvasive fibroblastsMacrophage populationsLungStromal cellsEpithelial cellsFibrosisCellular populationsDevelopmental markersSingle-cell RNA-seqPulmonary Complications of Immunotherapy
Bade BC, Possick JD. Pulmonary Complications of Immunotherapy. Clinics In Chest Medicine 2020, 41: 295-305. PMID: 32402364, DOI: 10.1016/j.ccm.2020.02.012.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsLung cancerImmune checkpoint inhibitor therapyImmune-related adverse eventsTreatment-limiting complicationsCheckpoint inhibitor therapyFurther prospective investigationMetastatic lung cancerFavorable safety profileTreatment of patientsPulmonary complicationsAdverse eventsClinical vigilanceInhibitor therapySignificant morbiditySafety profileProspective InvestigationCurrent guidelinesMortality riskImmunotherapyComplicationsPatientsCancerPneumonitisMorbidityChemotherapyTumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6
Arnal-Estapé A, Cai WL, Albert AE, Zhao M, Stevens LE, López-Giráldez F, Patel KD, Tyagi S, Schmitt EM, Westbrook TF, Nguyen DX. Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6. Oncogene 2020, 39: 3726-3737. PMID: 32157212, PMCID: PMC7190573, DOI: 10.1038/s41388-020-1246-z.Peer-Reviewed Original ResearchConceptsChromatin landscapeTranscription factorsBone morphogenetic protein (BMP) signalingDiverse transcriptional programsAlters chromatin accessibilityMultiple genomic lociMorphogenetic protein signalingDistal enhancer elementsSelective transcription factorsEpithelial cell typesSurfactant protein CChromatin accessibilityGenomic lociTranscriptional programsLung adenocarcinoma progressionTumor progressionEpigenetic mechanismsProtein signalingBiological functionsLUAD progressionLUAD cellsEnhancer elementsLineage dependencyTumor suppressionLung cancer cellsPlatform Effects on Regeneration by Pulmonary Basal Cells as Evaluated by Single-Cell RNA Sequencing
Greaney AM, Adams TS, Raredon M, Gubbins E, Schupp JC, Engler AJ, Ghaedi M, Yuan Y, Kaminski N, Niklason LE. Platform Effects on Regeneration by Pulmonary Basal Cells as Evaluated by Single-Cell RNA Sequencing. Cell Reports 2020, 30: 4250-4265.e6. PMID: 32209482, PMCID: PMC7175071, DOI: 10.1016/j.celrep.2020.03.004.Peer-Reviewed Original ResearchConceptsSingle-cell RNA sequencingBasal marker expressionBasal cellsChronic pulmonary diseaseRat tracheal epitheliumPulmonary diseaseRNA sequencingCell-based therapiesRat tracheaAir-liquid interfaceTissue graftMarker expressionTracheal epitheliumRegenerative outcomesTracheaEpithelial progenitorsDifferential outcomesEpitheliumOutcomesWhole organPopulation levelPlasma mitochondrial DNA is associated with extrapulmonary sarcoidosis
Ryu C, Brandsdorfer C, Adams T, Hu B, Kelleher DW, Yaggi M, Manning EP, Walia A, Reeves B, Pan H, Winkler J, Minasyan M, Dela Cruz CS, Kaminski N, Gulati M, Herzog EL. Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis. European Respiratory Journal 2019, 54: 1801762. PMID: 31273041, PMCID: PMC8088542, DOI: 10.1183/13993003.01762-2018.Peer-Reviewed Original ResearchConceptsExtrapulmonary diseaseMitochondrial DNAExtracellular mtDNABAL fluidAlpha-1 antitrypsin deficiencyPlasma mitochondrial DNAPlasma of patientsAfrican AmericansExtrapulmonary sarcoidosisSarcoidosis cohortSarcoidosis subjectsScadding stageAfrican American descentClinical featuresClinical findingsGranulomatous diseaseHealthy controlsAntitrypsin deficiencyGenomic researchHigher oddsSarcoidosisAggressive phenotypeMechanistic basisDiseaseTherapeutic insightsA functional macrophage migration inhibitory factor promoter polymorphism is associated with reduced diffusing capacity
Zhang C, Ramsey C, Berical A, Yu L, Leng L, McGinnis K, Song Y, Michael H, McCormack M, Allore H, Morris A, Crothers K, Bucala R, Lee P, Sauler M. A functional macrophage migration inhibitory factor promoter polymorphism is associated with reduced diffusing capacity. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2018, 316: l400-l405. PMID: 30520689, PMCID: PMC6397351, DOI: 10.1152/ajplung.00439.2018.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorChronic obstructive pulmonary diseaseMIF -794 CATTAbnormal diffusion capacityCigarette smoke exposureSmoke exposureAssociation of MIFDiffusion capacityMacrophage migration inhibitory factor (MIF) promoter polymorphismsPathogenesis of COPDChronic cigarette smoke exposureMultivariable logistic regression modelModifiable risk factorsObstructive pulmonary diseaseMigration inhibitory factorCross-sectional analysisLogistic regression modelsCommon genetic polymorphismsInnate immune genesAirflow obstructionMIF expressionCOPD severityPulmonary diseaseMIF allelesRisk factors
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