2024
Phage Therapy for Respiratory Infections: Opportunities and Challenges
Khosravi A, Chen Q, Echterhof A, Koff J, Bollyky P. Phage Therapy for Respiratory Infections: Opportunities and Challenges. Lung 2024, 202: 223-232. PMID: 38772946, DOI: 10.1007/s00408-024-00700-7.Peer-Reviewed Original ResearchChronic lung infectionLung infectionRespiratory infectionsAntimicrobial resistancePhage therapyClinical trialsPhage therapy clinical trialsProgressive respiratory failureChronic respiratory infectionsPersonalized phage therapyAntimicrobial resistant infectionsPost-antibiotic eraPotential of phagesSalvage therapyAdjuvant therapyRespiratory failureDisease resolutionChronic respiratory diseasesTreatment efficacyTherapyTherapeutic potentialIncreased mortalityInfectionNovel antibioticsPhageCystic Fibrosis Bacteriophage Study at Yale (CYPHY)
Stanley G, Cochrane C, Chan B, Kortright K, Rahman B, Lee A, Vill A, Sun Y, Stewart J, Britto-Leon C, Harris Z, Talwalker J, Shabanova V, Turner P, Koff J. Cystic Fibrosis Bacteriophage Study at Yale (CYPHY). 2024, a6808-a6808. DOI: 10.1164/ajrccm-conference.2024.209.1_meetingabstracts.a6808.Peer-Reviewed Original ResearchRole of Staphylococcus Aureus Superantigens in Cystic Fibrosis Lung Inflammation
Rajagopalan G, Tolentino J, Sun Y, Hu B, Koff J. Role of Staphylococcus Aureus Superantigens in Cystic Fibrosis Lung Inflammation. 2024, a6673-a6673. DOI: 10.1164/ajrccm-conference.2024.209.1_meetingabstracts.a6673.Peer-Reviewed Original ResearchEpidermal Growth Factor Receptor Regulates Beclin-1 in Hyperoxia-Induced Lung Injury
Harris Z, Sun Y, Korde A, Hu B, Sharma L, Manning E, Joerns J, Clark B, Stanley G, Shin H, Placek L, Unutmaz D, Chun H, Sauler M, Rajagopalan G, Zhang X, Wang H, Kang M, Koff J. Epidermal Growth Factor Receptor Regulates Beclin-1 in Hyperoxia-Induced Lung Injury. 2024, a6841-a6841. DOI: 10.1164/ajrccm-conference.2024.209.1_meetingabstracts.a6841.Peer-Reviewed Original ResearchLytic 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 strategyHuman iPSC-Based Model of COPD to Investigate Disease Mechanisms, Predict SARS-COV-2 Outcome, and Test Preventive Immunotherapy
Dagher R, Moldobaeva A, Gubbins E, Clark S, Alfajaro M, Wilen C, Hawkins F, Qu X, Chiang C, Li Y, Clarke L, Ikeda Y, Brown C, Kolbeck R, Ma Q, Rojas M, Koff J, Ghaedi M. Human iPSC-Based Model of COPD to Investigate Disease Mechanisms, Predict SARS-COV-2 Outcome, and Test Preventive Immunotherapy. Stem Cells 2024, 42: 230-250. PMID: 38183264, DOI: 10.1093/stmcls/sxad094.Peer-Reviewed Original ResearchSARS-CoV-2 infectionAlveolar nicheSARS-CoV-2 outcomesAberrant inflammatory responseModels of COPDDisease-specific mechanismsInflammation/Preventive immunotherapyChronic inflammationEpithelial damageInflammatory responseLung tissueCOPDNovel therapeuticsEpithelial-mesenchymal interactionsMitochondrial dysfunctionInfectionDisease mechanismsHuman iPSCCell deathFibroblast modelSingle-cell levelRepair mechanismsIPSCsImmunotherapy
2023
41 CYstic Fibrosis bacterioPHage study at Yale (CYPHY)
Chan B, Kortright K, Stanley G, Cochrane C, Lee A, Vill A, Sun Y, Stewart J, Britto-Leon C, Harris Z, Talkwalkar J, Shabanova V, Turner P, Koff J. 41 CYstic Fibrosis bacterioPHage study at Yale (CYPHY). Journal Of Cystic Fibrosis 2023, 22: s22. DOI: 10.1016/s1569-1993(23)00976-1.Peer-Reviewed Original Research43 Bacteriophages that kill Pseudomonas aeruginosa induce heterogenous cellular responses in the airway epithelium
Zamora P, Reidy T, Armbruster C, Turner P, Chan B, Koff J, Van Tyne D, Bomberger J. 43 Bacteriophages that kill Pseudomonas aeruginosa induce heterogenous cellular responses in the airway epithelium. Journal Of Cystic Fibrosis 2023, 22: s23-s24. DOI: 10.1016/s1569-1993(23)00978-5.Peer-Reviewed Original ResearchSpatiotemporally organized immunomodulatory response to SARS-CoV-2 virus in primary human broncho-alveolar epithelia
Castaneda D, Jangra S, Yurieva M, Martinek J, Callender M, Coxe M, Choi A, Diego J, Lin J, Wu T, Marches F, Chaussabel D, Yu P, Salner A, Aucello G, Koff J, Hudson B, Church S, Gorman K, Anguiano E, García-Sastre A, Williams A, Schotsaert M, Palucka K. Spatiotemporally organized immunomodulatory response to SARS-CoV-2 virus in primary human broncho-alveolar epithelia. IScience 2023, 26: 107374. PMID: 37520727, PMCID: PMC10374611, DOI: 10.1016/j.isci.2023.107374.Peer-Reviewed Original ResearchHuman air-liquid interface culturesAir-liquid interface culturesNucleoprotein expressionAirway epithelial cellsSARS-CoV-2 variant infectionResponse to virusesUnmet medical needCSF3 expressionInterface culturesImmune responseEpithelial cellsDay 4Severe diseaseVariant infectionBasal cellsTranscriptional signatureSARS-CoV-2InfectionApical cellsEarly responseMedical needSARS-CoV-2 virusEpitheliaVirusPost-infectionProtracted Pulmonary Inflammation in IFN-gamma Deficient Mice Recovering From Cytokine Release Syndrome
Rajagopalan G, Sun Y, Hu B, Harris Z, Stanely G, Koff J. Protracted Pulmonary Inflammation in IFN-gamma Deficient Mice Recovering From Cytokine Release Syndrome. 2023, a1386-a1386. DOI: 10.1164/ajrccm-conference.2023.207.1_meetingabstracts.a1386.Peer-Reviewed Original ResearchSingle Sequential Bacteriophage Therapy Decreases Pseudomonas Virulence More Than a Cocktail Approach
Stanley G, Chan B, Wuerstle S, Grun C, Kazmierczak B, Sun Y, Kortright K, Turner P, Koff J. Single Sequential Bacteriophage Therapy Decreases Pseudomonas Virulence More Than a Cocktail Approach. 2023, a1228-a1228. DOI: 10.1164/ajrccm-conference.2023.207.1_meetingabstracts.a1228.Peer-Reviewed Original ResearchA Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against Pseudomonas aeruginosa Infections
Geyer J, Krupa K, Harris Z, Sun Y, Sharma L, Würstle S, Hu B, Stanley G, Rajagopalan G, Pellot E, Koff J, Robinson J. A Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against Pseudomonas aeruginosa Infections. Antibiotics 2023, 12: 735. PMID: 37107097, PMCID: PMC10135120, DOI: 10.3390/antibiotics12040735.Peer-Reviewed Original ResearchMinimum inhibitory concentrationMinimum bactericidal concentrationCystic fibrosisAntiviral activityPseudomonas aeruginosa infectionLife-threatening infectionsAntibiotic-resistant infectionsDose-dependent responsePulmonary infectionPotent bactericidal activityAeruginosa infectionMouse lungPsA populationImmune systemVivo modelLung cellsPSA cellsHealth concernNovel therapeuticsInfectionLung modelH441 cellsOpportunistic bacterial pathogenSignificant decreaseInhibitory concentrationReport of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial
Consortium T, Files D, Aggarwal N, Albertson T, Auld S, Beitler J, Berger P, Burnham E, Calfee C, Cobb N, Crippa A, Discacciati A, Eklund M, Esserman L, Friedman E, Gandotra S, Khan K, Koff J, Kumar S, Liu K, Martin T, Matthay M, Meyer N, Obermiller T, Robinson P, Russell D, Thomas K, Wong F, Wunderink R, Wurfel M, Yen A, Youssef F, Darmanian A, Dzierba A, Garcia I, Gosek K, Madahar P, Mittel A, Muir J, Rosen A, Schicchi J, Serra A, Wahab R, Gibbs K, Landreth L, LaRose M, Parks L, Wynn A, Ittner C, Mangalmurti N, Reilly J, Harris D, Methukupally A, Patel S, Boerger L, Kazianis J, Higgins C, McKeehan J, Daniel B, Fields S, Hurst-Hopf J, Jauregui A, Swigart L, Blevins D, Nguyen C, Suarez A, Tanios M, Sarafian F, Shah U, Adelman M, Creel-Bulos C, Detelich J, Harris G, Nugent K, Spainhour C, Yang P, Haczku A, Hardy E, Harper R, Morrissey B, Sandrock C, Budinger G, Donnelly H, Singer B, Moskowitz A, Coleman M, Levitt J, Lu R, Henderson P, Asare A, Dunn I, Barragan A. Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial. EClinicalMedicine 2023, 58: 101889. PMID: 36883141, PMCID: PMC9981330, DOI: 10.1016/j.eclinm.2023.101889.Peer-Reviewed Original ResearchInvestigational agentsSevere COVID-19Hazard ratioModified intention-to-treat analysisEvaluating investigational agentsRegimen of dexamethasoneIntention-to-treat analysisBackbone regimensOpen-labelDornase alfaEfficacy signalsScreening of agentsScreening potential therapeuticsData monitoring committeeHigh morbidityAdaptive platform trialCOVID trialsMedical CentrePfizer Inc.Controlled trialsHospitalised patientsI-SPYPre-specified criteriaFast GrantTime-to-recoveryCOVID-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 resistancePatients