2024
Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells
Zamora P, Reidy T, Armbruster C, Sun M, Van Tyne D, Turner P, Koff J, Bomberger J. Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells. PLOS Biology 2024, 22: e3002566. PMID: 38652717, PMCID: PMC11037538, DOI: 10.1371/journal.pbio.3002566.Peer-Reviewed Original ResearchConceptsLytic phagesLytic bacteriophagesPhage therapyAirway epithelial cellsPseudomonas aeruginosa phagesEpithelial cellsMultidrug resistanceAirway epitheliumCystic fibrosisProinflammatory cytokinesHuman respiratory epithelial cellsPhage exposurePhage familiesMammalian cell responsesHuman airway epithelial cellsInternalized phageTreat multidrug-resistantPhageBacterial isolatesTranscriptional profilesRespiratory epithelial cellsHuman hostChronic respiratory disordersBacterial biofilmsBacteriophageNovel Approaches to Multidrug-Resistant Infections in Cystic Fibrosis
Murray T, Stanley G, Koff J. Novel Approaches to Multidrug-Resistant Infections in Cystic Fibrosis. Infectious Disease Clinics Of North America 2024, 38: 149-162. PMID: 38280761, DOI: 10.1016/j.idc.2023.12.002.Peer-Reviewed Original ResearchConceptsMultidrug-resistant organismsCystic fibrosis transmembrane conductance regulatorCystic fibrosisBeta-lactam/beta-lactamase combinationDevelopment of inhaled formulationsMethicillin-resistant Staphylococcus aureusTherapeutic approachesMultidrug-resistant organism infectionSystemic adverse eventsMultidrug-resistant infectionsTransmembrane conductance regulatorRespiratory tract infectionsCystic fibrosis patientsGram-negative organismsInnovative therapeutic approachesPulmonary infectionTract infectionsConductance regulatorBurkholderia sp.Multidrug resistanceAdverse eventsTreatment optionsAntibiotic resistanceFibrosis patientsOptimal doseOptimized preparation pipeline for emergency phage therapy against Pseudomonas aeruginosa at Yale University
Würstle S, Lee A, Kortright K, Winzig F, An W, Stanley G, Rajagopalan G, Harris Z, Sun Y, Hu B, Blazanin M, Hajfathalian M, Bollyky P, Turner P, Koff J, Chan B. Optimized preparation pipeline for emergency phage therapy against Pseudomonas aeruginosa at Yale University. Scientific Reports 2024, 14: 2657. PMID: 38302552, PMCID: PMC10834462, DOI: 10.1038/s41598-024-52192-3.Peer-Reviewed Original ResearchConceptsEvolutionary selection pressurePhage characterizationPhage therapyPersistent bacterial infectionsBacteriophage therapyPhageSelection pressurePseudomonas aeruginosaInvestigational new drug applicationBacterial infectionsNew Drug ApplicationTherapyDrug applicationClinical applicationAutographiviridaeBacteriaPotential strategy
2023
COVID-19 bacteremic co-infection is a major risk factor for mortality, ICU admission, and mechanical ventilation
Patton M, Orihuela C, Harrod K, Bhuiyan M, Dominic P, Kevil C, Fort D, Liu V, Farhat M, Koff J, Lal C, Gaggar A, Richter R, Erdmann N, Might M, Gaggar A. COVID-19 bacteremic co-infection is a major risk factor for mortality, ICU admission, and mechanical ventilation. Critical Care 2023, 27: 34. PMID: 36691080, PMCID: PMC9868503, DOI: 10.1186/s13054-023-04312-0.Peer-Reviewed Original ResearchConceptsBacterial co-infectionNeutrophil-to-lymphocyte ratioIn-hospital mortalityMechanical ventilationICU admissionCo-infectionRisk factorsSARS-CoV-2 variantsCohort studyIncreased riskPrimary outcomeIncreased risk of in-hospital mortalityRisk of in-hospital mortalityCommunity-acquired bacteremiaCulture-positive resultsRetrospective cohort studySingle-center reportsInpatient encountersMultivariate logistic regressionBlood culturesPrognostic indicatorOmicron SARS-CoV-2 variantComparison cohortOdds ratioSevere diseaseIFN-γ Is Protective in Cytokine Release Syndrome-associated Extrapulmonary Acute Lung Injury.
Sun Y, Hu B, Stanley G, Harris ZM, Gautam S, Homer R, Koff JL, Rajagopalan G. IFN-γ Is Protective in Cytokine Release Syndrome-associated Extrapulmonary Acute Lung Injury. American Journal Of Respiratory Cell And Molecular Biology 2023, 68: 75-89. PMID: 36125351, PMCID: PMC9817908, DOI: 10.1165/rcmb.2022-0117oc.Peer-Reviewed Original ResearchConceptsCytokine release syndromeAcute lung injuryExtrapulmonary acute lung injuryIFN-γ KO miceIL-17ALung injuryKO miceStaphylococcal enterotoxin BRelease syndromeIL-17A KO miceSevere acute lung injuryAcute respiratory distress syndromeSystemic T cell activationEnterotoxin BAdaptive T lymphocytesDR3 transgenic miceNeutralization of IFNRespiratory distress syndromeHuman leukocyte antigenRole of IFNT cell cytokinesJanus kinase inhibitorS100A8/A9T cell activationALI parametersBacteriophage Therapy for Pan-Drug-Resistant Pseudomonas aeruginosa in Two Persons With Cystic Fibrosis
Hahn A, Sami I, Chaney H, Koumbourlis A, Del Valle Mojica C, Cochrane C, Chan B, Koff J. Bacteriophage Therapy for Pan-Drug-Resistant Pseudomonas aeruginosa in Two Persons With Cystic Fibrosis. Journal Of Investigative Medicine High Impact Case Reports 2023, 11: 23247096231188243. PMID: 37515541, PMCID: PMC10387758, DOI: 10.1177/23247096231188243.Peer-Reviewed Original ResearchConceptsPulmonary exacerbationsCF transmembrane conductance regulator geneTransmembrane conductance regulator geneChronic bacterial colonizationRecurrent lung infectionsStructural lung damagePediatric clinical trialsLung function declineLung inflammationTreatment modalitiesLung infectionCystic fibrosisLung damageClinical trialsTherapeutic strategiesAntibiotic resistanceBacterial colonizationMonogenic diseasesBacteriophage therapyRegulated genesViscous secretionsReduced survivalFunctional declineExacerbationBacteriophage
2022
Inhaled Bacteriophage Therapy for Multi-Drug Resistant Achromobacter.
Winzig F, Gandhi S, Lee A, Würstle S, Stanley G, Capuano I, Neuringer I, Koff J, Turner P, Chan B. Inhaled Bacteriophage Therapy for Multi-Drug Resistant Achromobacter. The Yale Journal Of Biology And Medicine 2022, 95: 413-427. PMID: 36568830, PMCID: PMC9765334.Peer-Reviewed Original ResearchConceptsCF patientsCystic fibrosisChronic pulmonary infectionGlobal public health threatBacterial lung infectionsChallenging clinical problemPublic health threatChronic bacterial lung infectionsPulmonary infectionRespiratory statusLung infectionClinical problemBacteriophage therapyInfectionAntimicrobial-resistant bacteriaTherapyHealth threatPhage therapyPatientsAMR infectionsResistant bacteriaLytic bacteriophagesPossible benefitsChemical antibioticsCurrent studyNovel Approaches to Multidrug-Resistant Infections in Cystic Fibrosis
Murray T, Stanley G, Koff J. Novel Approaches to Multidrug-Resistant Infections in Cystic Fibrosis. Clinics In Chest Medicine 2022, 43: 667-676. PMID: 36344073, DOI: 10.1016/j.ccm.2022.06.008.Peer-Reviewed Original ResearchConceptsMultidrug-resistant organismsCystic fibrosisTherapeutic approachesNontuberculous mycobacteriaCystic fibrosis transmembrane conductance regulator (CFTR) dysfunctionSystemic adverse eventsRespiratory tract infectionsMethicillin-resistant Staphylococcus aureusAdditional clinical trialsNew treatment optionsPharmacokinetics/pharmacodynamicsInnovative therapeutic approachesMultidrug-resistant infectionsMDRO infectionAdverse eventsPulmonary infectionTract infectionsOptimal dosingTreatment optionsClinical trialsNew therapiesNegative organismsInfectionAntibiotic resistancePatientsEpidermal Growth Factor Receptor Inhibition Is Protective in Hyperoxia‐Induced Lung Injury
Harris ZM, Sun Y, Joerns J, Clark B, Hu B, Korde A, Sharma L, Shin HJ, Manning EP, Placek L, Unutmaz D, Stanley G, Chun H, Sauler M, Rajagopalan G, Zhang X, Kang MJ, Koff JL. Epidermal Growth Factor Receptor Inhibition Is Protective in Hyperoxia‐Induced Lung Injury. Oxidative Medicine And Cellular Longevity 2022, 2022: 9518592. PMID: 36193076, PMCID: PMC9526641, DOI: 10.1155/2022/9518592.Peer-Reviewed Original ResearchConceptsAcute lung injuryEpidermal growth factor receptorAlveolar epithelial cellsLung injurySevere hyperoxiaEGFR inhibitionEpithelial cellsHyperoxia-Induced Lung InjuryRole of EGFRMurine alveolar epithelial cellsGrowth factor receptor inhibitionWorse clinical outcomesEpidermal growth factor receptor inhibitionHuman alveolar epithelial cellsWild-type littermatesPoly (ADP-ribose) polymeraseTerminal dUTP nickGrowth factor receptorClinical outcomesImproved survivalReceptor inhibitionLung repairProtective roleComplex roleEGFR deletionI-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations
Files DC, Matthay MA, Calfee CS, Aggarwal NR, Asare AL, Beitler JR, Berger PA, Burnham EL, Cimino G, Coleman MH, Crippa A, Discacciati A, Gandotra S, Gibbs KW, Henderson PT, Ittner CAG, Jauregui A, Khan KT, Koff JL, Lang J, LaRose M, Levitt J, Lu R, McKeehan JD, Meyer NJ, Russell DW, Thomas KW, Eklund M, Esserman LJ, Liu KD, Esserman L, Calfee C, Liu K, Coleman M, Matthay M, Beitler J, Mittel A, Asare A, Yen A, Jauregui A, Crippa A, Suarez A, Serra A, Amin A, Rosen A, Dzierba A, Discacciati A, Haczku A, Barker A, Weisman A, Daniel B, Morrissey B, Ittner C, Jones C, Creel-Bulos C, Angelucci C, Files D, Russell D, Ng D, Burnham E, Youssef F, Chaparro-Rojas F, Harris G, Barot H, Su H, Garcia I, Sutter J, Dodin J, McKeehan J, Lee J, Kazianis J, Reilly J, Koff J, Detelich J, Lang J, Muir J, Thomas K, Khan K, Gosek K, Nugent K, Gibbs K, Yee K, Rodrigues L, Macias L, Orr L, Boerger L, Rosario-Remigio L, Kufa L, Huerta L, Tanios M, Reyes M, Eklund M, LaRose M, Adelman M, Juarez M, Jung M, Meyers M, Sternlieb M, Cobb N, Aggarwal N, Mangalmurti N, Meyer N, Jones P, Berger P, Henderson P, Saban P, Marshall P, Robinson P, Yang P, Madahar P, Nair R, Sonti R, Lee R, Wunderink R, Wahab R, Lupu R, Lu R, Kumar S, Auld S, Fields S, Wong F, Gandotra S, Pearson S, Whealon S, Albertson T, Obermiller T, Oliver T, Darmanian A, Schicchi J, Martinez E, Sarafian F, Nguyen J, Weiler-Lisowski B, Wyatt J, Blevins D, Melendrez M, Lopez B, Tzehaie H, Amosu O, Simonson A, Patel C, Levitt J, Hardy E, Lindgren B, Peterfreund G, Landreth L, Parks L, Aggarwal N. I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations. BMJ Open 2022, 12: e060664. PMID: 35667714, PMCID: PMC9170797, DOI: 10.1136/bmjopen-2021-060664.Peer-Reviewed Original ResearchConceptsSevere COVID-19COVID-19 trialsInvestigational agentsPlatform trialsCOVID-19 acute respiratory failureDefinitive efficacy trialAcute respiratory failureAdaptive platform trialPeer-reviewed medical journalsCOVID-19Novel effective therapeuticsCentral institutional review boardInstitutional review boardRespiratory failureIneffective therapyTherapeutic responseCommunity hospitalEfficacy trialsSerial studiesTrial designWake Forest SchoolEffective therapeuticsTrials NetworkPromising agentPatientsBronchial epithelium epithelial-mesenchymal plasticity forms aberrant basaloid-like cells in vitro
Uthaya Kumar DB, Motakis E, Yurieva M, Kohar V, Martinek J, Wu TC, Khoury J, Grassmann J, Lu M, Palucka K, Kaminski N, Koff JL, Williams A. Bronchial epithelium epithelial-mesenchymal plasticity forms aberrant basaloid-like cells in vitro. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2022, 322: l822-l841. PMID: 35438006, PMCID: PMC9142163, DOI: 10.1152/ajplung.00254.2021.Peer-Reviewed Original ResearchConceptsProtein codingEpithelial-mesenchymal transitionLncRNA genesEMT inductionSingle-cell RNA sequencingSingle-cell RNA-seq dataEpithelial-mesenchymal plasticityRNA-seq dataMechanisms of EMTSingle-cell levelEpithelial cell typesRole of EMTTranscriptional reprogrammingHuman bronchial epithelial cellsRNA genesEMT gene signatureTranscriptional changesTranscriptional differencesRNA sequencingSpecific lncRNAsBronchial epithelial cellsDifferential expressionMyofibroblast conversionCell typesGenesClinical trial design during and beyond the pandemic: the I-SPY COVID trial
Calfee C, Liu K, Asare A, Beitler J, Berger P, Coleman M, Crippa A, Discacciati A, Eklund M, Files D, Gandotra S, Gibbs K, Henderson P, Levitt J, Lu R, Matthay M, Meyer N, Russell D, Thomas K, Esserman L, Mittel A, Dzierba A, Madahar P, Serra A, Rosen A, Garcia I, Muir J, Schicchi J, Darmanian A, Wahab R, Gosek K, Auld S, Adelman M, Nugent K, Harris G, Creel-Bulos C, Yang P, Detelich J, Spainhour C, Cobb N, Sonti R, Orr L, Robinson P, Sarafian F, Martinez E, Jones P, Nguyen J, Obermiller T, Weiler-Lisowski B, Kufa L, Saba P, Wyatt J, Youssef F, Tanios M, Blevins D, Macias L, Suarez A, Reyes M, Jung M, Melendrez M, Rosario-Remigio L, Su H, Friedman E, Angelucci C, Chaparro-Rojas F, Sternlieb M, Sutter J, Whealon S, Nair R, Lopez B, Amosu O, Tzehaie H, Wunderink R, Patel C, Simonson A, Dodin J, Oliver T, Lupu R, Meyers M, Albertson T, Haczku A, Hardy E, Morrissey B, Juarez M, Pearson S, Lee R, Amin A, Jauregui A, Fields S, Ng D, Daniel B, Yee K, Jones C, Burnham E, McKeehan J, Ittner C, Reilly J, Mangalmurti N, Rodrigues L, Weisman A, Khan K, Wong S, Yen A, Peterfreund G, Kumar S, Marshall P, Huerta L, Lindgren B, Lee J, Barker A, Lang J, LaRose M, Landreth L, Parks L, Barot H, Koff J, Kazianis J, Boerger L. Clinical trial design during and beyond the pandemic: the I-SPY COVID trial. Nature Medicine 2022, 28: 9-11. PMID: 35058620, PMCID: PMC8922451, DOI: 10.1038/s41591-021-01617-x.Peer-Reviewed Original Research
2021
Bacteriophage therapy for infections in CF
Chan BK, Stanley G, Modak M, Koff JL, Turner PE. Bacteriophage therapy for infections in CF. Pediatric Pulmonology 2021, 56: s4-s9. PMID: 33434411, DOI: 10.1002/ppul.25190.Peer-Reviewed Original ResearchConceptsCystic fibrosisPhage therapyBacteriophage therapyBacterial pathogensAntibiotic-resistant bacterial infectionsPulmonary complicationsClinical benefitCase reportLung infectionClinical trialsDisease progressionTarget bacterial pathogensTherapyBacterial infectionsNovel management strategiesPatient treatmentPatient dataInfectionStaphylococcus aureusTrialsPseudomonas aeruginosaPotential usefulnessPathogensLytic phagesComplications
2020
Multi-dimensional clinical phenotyping of a national cohort of adult cystic fibrosis patients
Conrad D, Billings J, Teneback C, Koff J, Rosenbluth D, Bailey B, Jain R. Multi-dimensional clinical phenotyping of a national cohort of adult cystic fibrosis patients. Journal Of Cystic Fibrosis 2020, 20: 91-96. PMID: 32948498, DOI: 10.1016/j.jcf.2020.08.010.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorCF patientsCystic fibrosisClinical phenotypeChronic P. aeruginosa infectionDistal intestinal obstruction syndromeAdult cystic fibrosis patientsPseudomonas aeruginosa colonizationUS CF centersAdult CF patientsIntestinal obstruction syndromeTransmembrane conductance regulatorHigh-risk phenotypeWell-nourished groupCholestatic liver diseaseGroup of patientsCystic fibrosis patientsRates of pancreatic insufficiencyMulti-system disorderPancreatic malabsorptionObstruction syndromeChronic sinusitisConductance regulatorPancreatic insufficiencyCF centers
2019
Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria
Kortright KE, Chan BK, Koff JL, Turner PE. Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria. Cell Host & Microbe 2019, 25: 219-232. PMID: 30763536, DOI: 10.1016/j.chom.2019.01.014.Peer-Reviewed Original ResearchConceptsPhage therapyRecent case reportsAntibiotic-resistant bacteriaResistant bacterial infectionsCase reportChemical antibioticsClinical trialsClinical utilityIntractable infectionsAnimal modelsTherapyBacterial infectionsWestern medicineCombat Antibiotic-Resistant BacteriaPhage therapy researchInfectionAntibioticsTherapy researchPhage resistanceClinicTrials
2018
Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium
Kalinowski A, Galen B, Ueki I, Sun Y, Mulenos A, Osafo-Addo A, Clark B, Joerns J, Liu W, Nadel J, Dela Cruz C, Koff J. Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium. Mucosal Immunology 2018, 11: 958-967. PMID: 29411775, PMCID: PMC6431552, DOI: 10.1038/mi.2017.120.Peer-Reviewed Original ResearchConceptsRespiratory syncytial virusEpidermal growth factor receptorEGFR inhibitionGrowth factor receptorRSV infectionSyncytial virusViral infectionRegulatory factor 1Lower respiratory tract infectionsIFN-λ productionRespiratory tract infectionsChronic lung diseaseFactor receptorAntiviral immune responseFactor 1RSV F proteinType III IFNsAntiviral defenseEGFR activationInnate antiviral responseInterferon regulatory factor 1Cause pneumoniaRSV inducesSignificant IFNTyrosine kinase receptors
2017
Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice
Wong CK, Smith CA, Sakamoto K, Kaminski N, Koff JL, Goldstein DR. Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice. The Journal Of Immunology 2017, 199: 1060-1068. PMID: 28646038, PMCID: PMC5557035, DOI: 10.4049/jimmunol.1700397.Peer-Reviewed Original ResearchConceptsAlveolar macrophage phagocytosisInfluenza infectionAlveolar macrophagesLung damageMacrophage phagocytosisOlder peopleInfluenza-induced mortalityInfluenza viral infectionRetention of neutrophilsRespiratory virusesLung homeostasisLung infectionCell cycling pathwaysMurine modelViral infectionImpact immunityDefective phagocytosisApoptotic neutrophilsInfectionMacrophagesMortalityPhagocytosisNeutrophilsTranscriptional profilesCD204Cystic Fibrosis Transmembrane Regulator Modulators: Implications for the Management of Depression and Anxiety in Cystic Fibrosis
Talwalkar JS, Koff JL, Lee HB, Britto CJ, Mulenos AM, Georgiopoulos AM. Cystic Fibrosis Transmembrane Regulator Modulators: Implications for the Management of Depression and Anxiety in Cystic Fibrosis. Journal Of The Academy Of Consultation-Liaison Psychiatry 2017, 58: 343-354. PMID: 28576305, DOI: 10.1016/j.psym.2017.04.001.Peer-Reviewed Original ResearchConceptsCFTR modulator therapyCystic fibrosisModulator therapyNovel therapiesCF transmembrane regulatorCFTR modulatorsCentral nervous system functionNovel CF therapiesManagement of depressionWorse medical outcomesMental health specialistsDrug-drug interactionsNervous system functionMental health variablesTreatment guidelinesClinical outcomesMedication interactionsCF centersComorbid depressionCF RegistryAnxiety screeningCF teamNovel agentsHigh riskMedical outcomes
2015
Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation
Zhang PX, Cheng J, Zou S, D'Souza AD, Koff JL, Lu J, Lee PJ, Krause DS, Egan ME, Bruscia EM. Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation. Nature Communications 2015, 6: 6221. PMID: 25665524, PMCID: PMC4324503, DOI: 10.1038/ncomms7221.Peer-Reviewed Original ResearchConceptsCF macrophagesMiR-199aMicroRNA-199aHyper-inflammatory responseCFTR-deficient miceCystic fibrosis patientsCystic fibrosis lungLung destructionDisease morbidityPharmacological modulationCF miceCF lungFibrosis patientsInnate immunityLungMacrophagesCAV1 expressionDrug celecoxibReduced levelsTLR4CelecoxibMiceCav1PathwayMorbidity
2014
EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production
Kalinowski A, Ueki I, Min-Oo G, Ballon-Landa E, Knoff D, Galen B, Lanier LL, Nadel JA, Koff JL. EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2014, 307: l186-l196. PMID: 24838750, PMCID: PMC4101792, DOI: 10.1152/ajplung.00368.2013.Peer-Reviewed Original ResearchConceptsRespiratory viral infectionsRespiratory syncytial virusCXCL10 productionRespiratory virusesViral infectionIFN regulatory factorAirway epitheliumEGFR activationChronic obstructive pulmonary diseaseEpithelial cellsExacerbation of asthmaObstructive pulmonary diseaseRecruitment of lymphocytesAdaptive immune responsesAirway epithelial cellsNADPH oxidase activationInhibition of EGFRVirus-infected cellsHuman viral pathogensPulmonary diseaseSyncytial virusEpithelial productionIL-8Viral pneumoniaEpidermal growth factor receptor (EGFR) activation