2024
Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology
Phan H, Tsitsiklis A, Maguire C, Haddad E, Becker P, Kim-Schulze S, Lee B, Chen J, Hoch A, Pickering H, van Zalm P, Altman M, Augustine A, Calfee C, Bosinger S, Cairns C, Eckalbar W, Guan L, Jayavelu N, Kleinstein S, Krammer F, Maecker H, Ozonoff A, Peters B, Rouphael N, Montgomery R, Reed E, Schaenman J, Steen H, Levy O, Diray-Arce J, Langelier C, Erle D, Hendrickson C, Kangelaris K, Nguyen V, Lee D, Chak S, Ghale R, Gonzalez A, Jauregui A, Leroux C, Altamirano L, Rashid A, Willmore A, Woodruff P, Krummel M, Carrillo S, Ward A, Patel R, Wilson M, Dandekar R, Alvarenga B, Rajan J, Schroeder A, Fragiadakis G, Mick E, Guerrero Y, Love C, Maliskova L, Adkisson M, Ehrlich L, Melamed E, Rousseau J, Hurley K, Geltman J, Siles N, Rogers J, Kutzler M, Bernui M, Cusimano G, Connors J, Woloszczuk K, Joyner D, Edwards C, Lin E, Melnyk N, Powell D, Kim J, Goonewardene I, Simmons B, Smith C, Martens M, Croen B, Semenza N, Bell M, Furukawa S, McLin R, Tegos G, Rogowski B, Mege N, Ulring K, Holland S, Rosen L, Lee S, Vaysman T, Fernandez-Sesma A, Simon V, Van Bakel H, Gonzalez-Reiche A, Qi J, Carreño J, Singh G, Raskin A, Tcheou J, Khalil Z, van de Guchte A, Farrugia K, Khan Z, Kelly G, Srivastava K, Eaker L, Bermúdez González M, Mulder L, Beach K, Fatou B, Smolen K, Viode A, van Haren S, Jha M, Kho A, Milliren C, Chang A, McEnaney K, Barton B, Lentucci C, Murphy M, Saluvan M, Shaheen T, Liu S, Syphurs C, Albert M, Hayati A, Bryant R, Abraham J, Salehi-Rad R, Rivera A, Sen S, Elashoff D, Ward D, Presnell S, Kohr B, Arnett A, Boddapati A, Tharp G, Pellegrini K, Johnson B, Panganiban B, Huerta C, Anderson E, Samaha H, Sevransky J, Bristow L, Beagle E, Cowan D, Hamilton S, Hodder T, Esserman D, Brito A, Rothman J, Grubaugh N, Ko A, Hafler D, Shaw A, Gygi J, Pawar S, Konstorum A, Chen E, Cotsapas C, Wang X, Xu L, Dela Cruz C, Iwasaki A, Mohanty S, Nelson A, Zhao Y, Farhadian S, Asashima H, Pulendran B, Nadeau R, Rosenberg-Hasson Y, Leipold M, Sigal N, Rogers A, Fernandez A, Manohar M, Do E, Chang I, Vita R, Westendorf K, Corry D, Kheradmand F, Song L, Nelson E, Baden L, Mendez K, Lasky-Su J, Tong A, Rooks R, Sekaly R, Fourati S, McComsey G, Harris P, Sieg S, Ribeiro S, Overton J, Rahman A, Hutton S, Michelotti G, Wong K, Seyfert-Margolis V, Metcalf J, Agudelo Higuita N, Sinko L, Booth J, Messer W, Hough C, Siegel S, Sullivan P, Lu Z, Kraft M, Bime C, Mosier J, Erickson H, Schunk R, Kimura H, Conway M, Atkinson M, Brakenridge S, Ungaro R, Manning B, Oberhaus J, Guirgis F, Borresen B, Anderson M. Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology. Science Translational Medicine 2024, 16: eadj5154. PMID: 38630846, DOI: 10.1126/scitranslmed.adj5154.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overChemokinesCOVID-19HumansMiddle AgedMultiomicsProspective StudiesSARS-CoV-2Young AdultConceptsPro-inflammatory genesViral clearanceUpper airwayImmune signaling pathwaysInduction of pro-inflammatory genesBiomarkers of disease severityDelayed viral clearanceImpaired viral clearanceSevere coronavirus disease 2019B cell populationsAge-dependent up-regulationExpression of pro-inflammatory genesHost immune responseSignaling pathwayType I interferon gene expressionCOVID-19 immunopathologyInnate immune signaling pathwaysSerum chemokinesAge-dependent impairmentNaive TMulticenter cohortNasal transcriptomeAcute respiratory syndrome coronavirus 2Monocyte populationsSerum protein profiles
2020
Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis.
Schupp JC, Khanal S, Gomez JL, Sauler M, Adams TS, Chupp GL, Yan X, Poli S, Zhao Y, Montgomery RR, Rosas IO, Dela Cruz CS, Bruscia EM, Egan ME, Kaminski N, Britto CJ. Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2020, 202: 1419-1429. PMID: 32603604, PMCID: PMC7667912, DOI: 10.1164/rccm.202004-0991oc.Peer-Reviewed Original ResearchConceptsCF lung diseaseHealthy control subjectsImmune dysfunctionLung diseaseCystic fibrosisControl subjectsSputum cellsAbnormal chloride transportLung mononuclear phagocytesInnate immune dysfunctionDivergent clinical coursesImmune cell repertoireMonocyte-derived macrophagesCF monocytesAirway inflammationClinical courseProinflammatory featuresCell survival programInflammatory responseTissue injuryCell repertoireImmune functionTranscriptional profilesAlveolar macrophagesMononuclear phagocytes
2017
Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes
Molony RD, Nguyen JT, Kong Y, Montgomery RR, Shaw AC, Iwasaki A. Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes. Science Signaling 2017, 10 PMID: 29233916, PMCID: PMC6429941, DOI: 10.1126/scisignal.aan2392.Peer-Reviewed Original ResearchConceptsType I IFNsI IFNsI interferonOlder adultsIFN inductionRetinoic acid-inducible gene IAcid-inducible gene IHealthy human donorsType I interferonRespiratory influenzaProinflammatory cytokinesVirus infectionType I IFN genesAdult monocytesAntiviral resistanceTranscription factor IRF8IFN responseHuman donorsMonocytesIncreased proteasomal degradationHuman monocytesYoung adultsIRF8 expressionIAV RNAInfected cellsThe natural killer cell response to West Nile virus in young and old individuals with or without a prior history of infection
Yao Y, Strauss-Albee DM, Zhou JQ, Malawista A, Garcia MN, Murray KO, Blish CA, Montgomery RR. The natural killer cell response to West Nile virus in young and old individuals with or without a prior history of infection. PLOS ONE 2017, 12: e0172625. PMID: 28235099, PMCID: PMC5325267, DOI: 10.1371/journal.pone.0172625.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsAgedAged, 80 and overAntigens, CDAsymptomatic DiseasesFemaleGene Expression RegulationHumansImmunity, InnateImmunophenotypingInterferon-gammaKiller Cells, NaturalLymphocyte ActivationLymphocyte CountMiddle AgedNatural Cytotoxicity Triggering Receptor 1Natural Cytotoxicity Triggering Receptor 2Natural Cytotoxicity Triggering Receptor 3NK Cell Lectin-Like Receptor Subfamily CNK Cell Lectin-Like Receptor Subfamily KPrimary Cell CultureSeverity of Illness IndexWest Nile FeverWest Nile virusConceptsNK cell subsetsNK cellsWest Nile virusWNV infectionCell subsetsCell responsesSpecific NK cell subsetsNatural killer cell responsesInnate NK cellsSevere neuroinvasive diseaseNK cell responsesNK cell receptorsNile virusHuman WNV infectionsImmune pathogenesisNK repertoirePolyfunctional responsesMore IFNSymptomatic infectionChemokine secretionAsymptomatic infectionNeuroinvasive diseasePrior historyCytolytic activityInfection
2016
Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease
Pillai PS, Molony RD, Martinod K, Dong H, Pang IK, Tal MC, Solis AG, Bielecki P, Mohanty S, Trentalange M, Homer RJ, Flavell RA, Wagner DD, Montgomery RR, Shaw AC, Staeheli P, Iwasaki A. Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science 2016, 352: 463-466. PMID: 27102485, PMCID: PMC5465864, DOI: 10.1126/science.aaf3926.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdultAgedAged, 80 and overAnimalsBacterial InfectionsCaspase 1CaspasesCaspases, InitiatorFemaleHumansImmunity, InnateInfluenza A virusInfluenza, HumanInterferon-betaMaleMembrane GlycoproteinsMiceMonocytesMyxovirus Resistance ProteinsNeutrophilsOrthomyxoviridae InfectionsRespiratory Tract InfectionsToll-Like Receptor 7Viral LoadYoung AdultConceptsBacterial burdenAntiviral resistanceNeutrophil-dependent tissue damageMyD88-dependent signalingAntiviral interferon productionCaspase-1/11IAV diseaseViral loadInfluenza diseaseOlder humansTissue damageInterferon productionInflammasome responseOlder adultsTLR7Vivo consequencesDiseaseMiceIAVBurdenMx geneHumansMonocytesMortalityInfluenza
2014
Systems Immunology Reveals Markers of Susceptibility to West Nile Virus Infection
Qian F, Goel G, Meng H, Wang X, You F, Devine L, Raddassi K, Garcia MN, Murray KO, Bolen CR, Gaujoux R, Shen-Orr SS, Hafler D, Fikrig E, Xavier R, Kleinstein SH, Montgomery RR. Systems Immunology Reveals Markers of Susceptibility to West Nile Virus Infection. MSphere 2014, 22: 6-16. PMID: 25355795, PMCID: PMC4278927, DOI: 10.1128/cvi.00508-14.Peer-Reviewed Original ResearchConceptsWest Nile virus infectionVirus infectionMyeloid dendritic cellsMarker of susceptibilityPotential therapeutic strategySeverity of infectionSevere neurological diseaseOlder patientsAcute infectionDendritic cellsCXCL10 expressionDetectable yearsImmunity-related genesStratified cohortWNV infectionTherapeutic strategiesPathogenic mechanismsAnimal studiesNeurological diseasesDisease severityVivo infectionPredictive signatureInfectionProminent alterationsPrimary cellsReduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging
Qian F, Guo X, Wang X, Yuan X, Chen S, Malawista SE, Bockenstedt LK, Allore HG, Montgomery RR. Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging. Aging 2014, 6: 131-139. PMID: 24595889, PMCID: PMC3969281, DOI: 10.18632/aging.100642.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAgingEnergy MetabolismFemaleHumansMaleNeutrophilsToll-Like Receptor 1Young AdultConceptsToll-like receptor 1Polymorphonuclear leukocytesOlder adultsChemokine IL-8Loss of CD62LAge-dependent deficienciesPotential therapeutic opportunitiesHuman polymorphonuclear leukocytesTLR1 expressionIL-8PMN functionPMN activationMultiple pathwaysImmune functionYoung donorsP38 MAP kinaseReceptor 1Bacterial infectionsTherapeutic opportunitiesProgressive declineGlucose uptakeReduced expressionAdultsStimulationLeukocytesImmune Markers Associated with Host Susceptibility to Infection with West Nile Virus
Qian F, Thakar J, Yuan X, Nolan M, Murray KO, Lee WT, Wong SJ, Meng H, Fikrig E, Kleinstein SH, Montgomery RR. Immune Markers Associated with Host Susceptibility to Infection with West Nile Virus. Viral Immunology 2014, 27: 39-47. PMID: 24605787, PMCID: PMC3949440, DOI: 10.1089/vim.2013.0074.Peer-Reviewed Original ResearchConceptsWest Nile virusSevere infectionsImmune markersIL-4IL-4 levelsSerum cytokine levelsSerum IL-4Nile virusSignificant risk factorsImmune system statusPeripheral blood cellsSevere neurological diseaseCytokine levelsAntibody levelsImmune statusRisk factorsHealthy subjectsStratified cohortWNV infectionNeurological diseasesInfectionAltered expression levelsBlood cellsAltered gene expression patternsHost susceptibility
2011
Age‐associated elevation in TLR5 leads to increased inflammatory responses in the elderly
Qian F, Wang X, Zhang L, Chen S, Piecychna M, Allore H, Bockenstedt L, Malawista S, Bucala R, Shaw AC, Fikrig E, Montgomery RR. Age‐associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging Cell 2011, 11: 104-110. PMID: 22023165, PMCID: PMC3257374, DOI: 10.1111/j.1474-9726.2011.00759.x.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAgingExtracellular Signal-Regulated MAP KinasesFemaleHumansInflammationInterleukin-8MaleMiddle AgedMonocytesMultivariate AnalysisNF-kappa BP38 Mitogen-Activated Protein KinasesPhosphorylationProtein TransportRNA, MessengerSignal TransductionToll-Like Receptor 5Tumor Necrosis Factor-alphaConceptsToll-like receptorsIL-8Multivariable mixed-effects modelsOlder individualsElevated IL-8Levels of TLR5Expression of TLR5Production of TNFAge-associated elevationAge-related decreaseDendritic cellsImmune responsivenessElderly donorsInflammatory responseImmune functionNF-κBTLR5Progressive declineMonocytesMixed effects modelsMAPK p38Significant increaseEffects modelAssociated increaseCritical mechanismImpaired Interferon Signaling in Dendritic Cells From Older Donors Infected In Vitro With West Nile Virus
Qian F, Wang X, Zhang L, Lin A, Zhao H, Fikrig E, Montgomery RR. Impaired Interferon Signaling in Dendritic Cells From Older Donors Infected In Vitro With West Nile Virus. The Journal Of Infectious Diseases 2011, 203: 1415-1424. PMID: 21398396, PMCID: PMC3080893, DOI: 10.1093/infdis/jir048.Peer-Reviewed Original ResearchConceptsDendritic cellsWest Nile virusOlder donorsAntiviral responseToll-like receptor 3Initial antiviral responseLate-phase responseNile virusSignificant age-related differencesSignificant human morbidityType I IFNQuantified cytokinesRNA flavivirusAge-related differencesYoung donorsI IFNReceptor RIGViral infectionReceptor 3Human morbidityOlder populationCritical regulatory pathwaysInterferon SignalingNuclear translocationDefective regulation
2010
Dysregulation of human Toll-like receptor function in aging
Shaw AC, Panda A, Joshi SR, Qian F, Allore HG, Montgomery RR. Dysregulation of human Toll-like receptor function in aging. Ageing Research Reviews 2010, 10: 346-353. PMID: 21074638, PMCID: PMC3633557, DOI: 10.1016/j.arr.2010.10.007.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overAgingDendritic CellsHumansImmunity, InnateMacrophagesSignal TransductionToll-Like ReceptorsConceptsToll-like receptorsTLR functionImmune systemToll-like receptor functionPattern recognition receptor familyAge-associated dysregulationInnate immune systemGeriatric patientsTLR activationAnimal modelsContext of agingReceptor functionHuman cohortsInfectious diseasesReceptor familyInappropriate persistenceDysregulationRecent studiesOverarching themesAdaptive responseMorbidityImmunosenescencePatientsCohortInnateAge-Associated Decrease in TLR Function in Primary Human Dendritic Cells Predicts Influenza Vaccine Response
Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E, Allore HG, Montgomery RR, Shaw AC. Age-Associated Decrease in TLR Function in Primary Human Dendritic Cells Predicts Influenza Vaccine Response. The Journal Of Immunology 2010, 184: 2518-2527. PMID: 20100933, PMCID: PMC3867271, DOI: 10.4049/jimmunol.0901022.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsAgedAged, 80 and overAntibodies, ViralCytokinesDendritic CellsFemaleFlow CytometryHumansInfluenza A Virus, H1N1 SubtypeInfluenza VaccinesInterleukin-12 Subunit p40Interleukin-6Linear ModelsMaleMiddle AgedReverse Transcriptase Polymerase Chain ReactionToll-Like ReceptorsTumor Necrosis Factor-alphaYoung AdultConceptsPrimary human dendritic cellsDendritic cellsHuman dendritic cellsMyeloid DCsPlasmacytoid DCsCytokine productionTLR functionTNF-alphaIntracellular cytokine productionPoor Ab responsesInfluenza vaccine responsesMyeloid dendritic cellsPlasmacytoid dendritic cellsYoung individualsIntracellular cytokine stainingIL-12 productionIFN-alpha productionTLR ligand stimulationTLR gene expressionInnate immune responseAge-Associated DecreaseTLR8 engagementInfluenza immunizationAge-associated effectsCytokine staining
2009
Human innate immunosenescence: causes and consequences for immunity in old age
Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC. Human innate immunosenescence: causes and consequences for immunity in old age. Trends In Immunology 2009, 30: 325-333. PMID: 19541535, PMCID: PMC4067971, DOI: 10.1016/j.it.2009.05.004.Peer-Reviewed Original ResearchConceptsInnate immune system initiatesNatural killer T cellsOlder ageAntiviral cytokine productionKiller T cellsInnate immune responseInnate immune systemDendritic cellsNatural killerCytokine productionHuman immunosenescenceT cellsImmune responseAdaptive immunityImmune systemInnate immunityImmunityAgeCellsDiverse cellsImmunosenescenceVaccinationNeutrophilsMonocytesInfection
2008
Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly
Kong KF, Delroux K, Wang X, Qian F, Arjona A, Malawista SE, Fikrig E, Montgomery RR. Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly. Journal Of Virology 2008, 82: 7613-7623. PMID: 18508883, PMCID: PMC2493309, DOI: 10.1128/jvi.00618-08.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsAgedAged, 80 and overCell Adhesion MoleculesCell LineCells, CulturedCytokinesFemaleHumansImmunity, InnateLectins, C-TypeMacrophagesMaleMiddle AgedNorth AmericaProtein BindingReceptors, Cell SurfaceSTAT1 Transcription FactorToll-Like Receptor 3Viral Envelope ProteinsWest Nile FeverWest Nile virusConceptsInnate immune responseToll-like receptor 3Intercellular adhesion molecule 3West Nile virusImmune responseYoung donorsC-type lectin dendritic cell-specific intercellular adhesion molecule 3Dendritic cell-specific intercellular adhesion molecule 3Nile virusBlood-brain barrierWNV envelope proteinSevere neurological diseaseResponsiveness of macrophagesPrimary human macrophagesCytokine levelsOlder donorsWNV infectionNeurological diseasesReceptor 3Human macrophagesOlder individualsElevated levelsMacrophagesMolecule 3Significant differences