Featured Publications
Reinventing positive-strand RNA virus reverse genetics
Lindenbach BD. Reinventing positive-strand RNA virus reverse genetics. Advances In Virus Research 2022, 112: 1-29. PMID: 35840179, PMCID: PMC9273853, DOI: 10.1016/bs.aivir.2022.03.001.Chapters
2024
SARS-CoV-2-related bat viruses evade human intrinsic immunity but lack efficient transmission capacity
Peña-Hernández M, Alfajaro M, Filler R, Moriyama M, Keeler E, Ranglin Z, Kong Y, Mao T, Menasche B, Mankowski M, Zhao Z, Vogels C, Hahn A, Kalinich C, Zhang S, Huston N, Wan H, Araujo-Tavares R, Lindenbach B, Homer R, Pyle A, Martinez D, Grubaugh N, Israelow B, Iwasaki A, Wilen C. SARS-CoV-2-related bat viruses evade human intrinsic immunity but lack efficient transmission capacity. Nature Microbiology 2024, 9: 2038-2050. PMID: 39075235, DOI: 10.1038/s41564-024-01765-z.Peer-Reviewed Original ResearchBat coronavirusesRelatives of SARS-CoV-2Upper airwayUpper airways of miceEpithelial cellsHuman nasal epithelial cellsAirways of miceMajor histocompatibility complex class I.SARS-CoV-2Nasal epithelial cellsHistocompatibility complex class I.Human bronchial epithelial cellsGenetic similarityBronchial epithelial cellsInnate immune restrictionCoronavirus replicationFunctional characterizationMolecular cloningReduced pathogenesisImpaired replicationBat virusCoronavirus pathogenesisPandemic potentialHigh-risk familiesImmune restrictionProof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid
Papini C, Ullah I, Ranjan A, Zhang S, Wu Q, Spasov K, Zhang C, Mothes W, Crawford J, Lindenbach B, Uchil P, Kumar P, Jorgensen W, Anderson K. Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2320713121. PMID: 38621119, PMCID: PMC11046628, DOI: 10.1073/pnas.2320713121.Peer-Reviewed Original ResearchConceptsDirect-acting antiviralsSARS-CoV-2Lack of off-target effectsIn vitro pharmacological profileTreatment of patientsDevelopment of severe symptomsPharmacological propertiesDrug-drug interactionsSARS-CoV-2 infectionProof-of-concept studySARS-CoV-2 M<sup>pro</sup>.Combination regimenImmunocompromised patientsLead compoundsSARS-CoV-2 main proteaseOral doseActive drugTreat infectionsPharmacological profileSARS-CoV-2 MPotential preclinical candidateOff-target effectsPatientsComplete recoveryCapsule formulationPrior Influenza Infection Mitigates SARS-CoV-2 Disease in Syrian Hamsters
Di Pietro C, Haberman A, Lindenbach B, Smith P, Bruscia E, Allore H, Vander Wyk B, Tyagi A, Zeiss C. Prior Influenza Infection Mitigates SARS-CoV-2 Disease in Syrian Hamsters. Viruses 2024, 16: 246. PMID: 38400021, PMCID: PMC10891789, DOI: 10.3390/v16020246.Peer-Reviewed Original ResearchConceptsTransient gene expressionSARS-CoV-2Viral replication pathwayReplication pathwayAntiviral pathwaysEndemism patternsUpregulation of innateGene expressionQuantitative RT-PCRMitigated weight lossDual-infected animalsSARS-CoV-2 viral loadSARS-CoV-2 infectionSyrian hamstersSeasonal infection ratesSARS-CoV-2 inoculationLungs of animalsIndividual virusesSARS-CoV-2 diseaseUpper respiratory tractH1N1 infectionRT-PCRBronchoalveolar lavageViral loadCytokine levelsVirology—the path forward
Rasmussen A, Gronvall G, Lowen A, Goodrum F, Alwine J, Andersen K, Anthony S, Baines J, Banerjee A, Broadbent A, Brooke C, Campos S, Caposio P, Casadevall A, Chan G, Cliffe A, Collins-McMillen D, Connell N, Damania B, Daugherty M, Debbink K, Dermody T, DiMaio D, Duprex W, Emerman M, Galloway D, Garry R, Goldstein S, Greninger A, Hartman A, Hogue B, Horner S, Hotez P, Jung J, Kamil J, Karst S, Laimins L, Lakdawala S, Landais I, Letko M, Lindenbach B, Liu S, Luftig M, McFadden G, Mehle A, Morrison J, Moscona A, Mühlberger E, Munger J, Münger K, Murphy E, Neufeldt C, Nikolich J, O'Connor C, Pekosz A, Permar S, Pfeiffer J, Popescu S, Purdy J, Racaniello V, Rice C, Runstadler J, Sapp M, Scott R, Smith G, Sorrell E, Speranza E, Streblow D, Tibbetts S, Toth Z, Van Doorslaer K, Weiss S, White E, White T, Wobus C, Worobey M, Yamaoka S, Yurochko A. Virology—the path forward. Journal Of Virology 2024, 98: e01791-23. PMID: 38168672, PMCID: PMC10804978, DOI: 10.1128/jvi.01791-23.Peer-Reviewed Original Research
2023
Astrovirus replication is dependent on induction of double-membrane vesicles through a PI3K-dependent, LC3-independent pathway
Bub T, Hargest V, Tan S, Smith M, Vazquez-Pagan A, Flerlage T, Brigleb P, Meliopoulos V, Lindenbach B, Ramanathan H, Cortez V, Crawford J, Schultz-Cherry S. Astrovirus replication is dependent on induction of double-membrane vesicles through a PI3K-dependent, LC3-independent pathway. Journal Of Virology 2023, 97: e01025-23. PMID: 37668367, PMCID: PMC10537808, DOI: 10.1128/jvi.01025-23.Peer-Reviewed Original ResearchConceptsAstrovirus infectionAstrovirus replicationPromising therapeutic optionPositive-sense RNA virus infectionPotential antiviral targetsRNA virusesRNA virus infectionCritical new evidenceGastrointestinal symptomsTherapeutic optionsPositive-sense RNA virusesVirus infectionTherapeutic interventionsAntiviral targetViral replicationDMV formationInfectionGenetic inhibitionReplication organellesHuman astrovirusPI3KPotential targetEarly componentPatientsAutophagy machinery
2022
The In Vivo and In Vitro Architecture of the Hepatitis C Virus RNA Genome Uncovers Functional RNA Secondary and Tertiary Structures
Wan H, Adams RL, Lindenbach BD, Pyle AM. The In Vivo and In Vitro Architecture of the Hepatitis C Virus RNA Genome Uncovers Functional RNA Secondary and Tertiary Structures. Journal Of Virology 2022, 96: e01946-21. PMID: 35353000, PMCID: PMC9044954, DOI: 10.1128/jvi.01946-21.Peer-Reviewed Original ResearchConceptsSecondary structure mapRNA genomeRNA structureTertiary structureProtein-coding genesPositive-strand RNA virusesRegulatory RNA structuresFull-length structureHCV RNA genomeValuable model systemRNA structural motifsSecondary structural elementsEvolutionary functional analysisLife cycleVirus life cycleCellular contextCorresponding transcriptsImportant human pathogenLong RNAsGenomeSame RNAGenomic RNAComprehensive atlasFunctional analysisFunctional importanceDe novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report
Gandhi S, Klein J, Robertson AJ, Peña-Hernández MA, Lin MJ, Roychoudhury P, Lu P, Fournier J, Ferguson D, Mohamed Bakhash SAK, Catherine Muenker M, Srivathsan A, Wunder EA, Kerantzas N, Wang W, Lindenbach B, Pyle A, Wilen CB, Ogbuagu O, Greninger AL, Iwasaki A, Schulz WL, Ko AI. De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report. Nature Communications 2022, 13: 1547. PMID: 35301314, PMCID: PMC8930970, DOI: 10.1038/s41467-022-29104-y.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionVirologic responsePersistent SARS-CoV-2 infectionResistance mutationsPre-treatment specimensB-cell deficiencyRemdesivir resistanceRemdesivir therapyViral sheddingCase reportAntiviral agentsPatientsCombinatorial therapyInfectionTherapyWhole-genome sequencingTreatmentImportance of monitoringDe novo emergenceFold increaseRNA-dependent RNA polymeraseNovo emergencePotential benefitsMutationsIndolent
2021
Placenta-derived interferon-stimulated gene 20 controls ZIKA virus infection
Ding J, Aldo P, Roberts CM, Stabach P, Liu H, You Y, Qiu X, Jeong J, Maxwell A, Lindenbach B, Braddock D, Liao A, Mor G. Placenta-derived interferon-stimulated gene 20 controls ZIKA virus infection. EMBO Reports 2021, 22: embr202152450. PMID: 34405956, PMCID: PMC8490983, DOI: 10.15252/embr.202152450.Peer-Reviewed Original ResearchConceptsZika virus infectionVirus infectionTrophoblast cellsPotential immune modulatory functionsInterferon-stimulated gene 20Anti-viral treatmentHigh-risk populationImmune modulatory functionsAnti-viral responseZika viral infectionImportance of preventionPregnant womenReplacement therapyViral infectionFetal developmentZika virusViral titersModulatory functionViral replicationInfectionAdverse effectsGene 20PregnancyPlacentaRNA virusesOptimization of Triarylpyridinone Inhibitors of the Main Protease of SARS-CoV‑2 to Low-Nanomolar Antiviral Potency
Zhang CH, Spasov KA, Reilly RA, Hollander K, Stone EA, Ippolito JA, Liosi ME, Deshmukh MG, Tirado-Rives J, Zhang S, Liang Z, Miller SJ, Isaacs F, Lindenbach BD, Anderson KS, Jorgensen WL. Optimization of Triarylpyridinone Inhibitors of the Main Protease of SARS-CoV‑2 to Low-Nanomolar Antiviral Potency. ACS Medicinal Chemistry Letters 2021, 12: 1325-1332. PMID: 34408808, PMCID: PMC8291137, DOI: 10.1021/acsmedchemlett.1c00326.Peer-Reviewed Original ResearchRestriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshifting
Sun Y, Abriola L, Niederer RO, Pedersen SF, Alfajaro MM, Silva Monteiro V, Wilen CB, Ho YC, Gilbert WV, Surovtseva YV, Lindenbach BD, Guo JU. Restriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshifting. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2023051118. PMID: 34185680, PMCID: PMC8256030, DOI: 10.1073/pnas.2023051118.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 replicationSARS-CoV-2Severe acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Syndrome coronavirus 2Vero E6 cellsHigh-throughput compound screenOpen reading frame 1bEffective antiviral strategiesCoronavirus 2E6 cellsAntiviral strategiesViral gene expressionCompound screenFluoroquinolone antibacterialsFrame 1bGene expressionPotent Noncovalent Inhibitors of the Main Protease of SARS-CoV‑2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations
Zhang CH, Stone EA, Deshmukh M, Ippolito JA, Ghahremanpour MM, Tirado-Rives J, Spasov KA, Zhang S, Takeo Y, Kudalkar SN, Liang Z, Isaacs F, Lindenbach B, Miller SJ, Anderson KS, Jorgensen WL. Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV‑2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations. ACS Central Science 2021, 7: 467-475. PMID: 33786375, PMCID: PMC7931627, DOI: 10.1021/acscentsci.1c00039.Peer-Reviewed Original ResearchFree energy perturbation calculationsX-ray crystal structurePotent noncovalent inhibitorMain proteaseHigh-resolution X-ray crystal structuresCell-based antiviral assaysComputational chemistryLigand complexesNoncovalent inhibitorsCrystal structureNonpeptidic inhibitorsLead optimizationDrug discoveryPerturbation calculationsNM ICPotent analoguesKinetic assaysPossible therapeutic significanceNoncovalentChemistryAnaloguesValuable guidanceCalculationsCompoundsComplexes
2020
Enabling HCV replication in cell culture: An approach for vaccine and drug development
Ngounoue M, Ndjomou J, Lindenbach B. Enabling HCV replication in cell culture: An approach for vaccine and drug development. International Journal Of Infectious Diseases 2020, 101: 510. DOI: 10.1016/j.ijid.2020.09.1325.Peer-Reviewed Original ResearchA Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating
Zhang S, Ramanathan H, Douam F, Mar K, Chang J, Yang P, Schoggins J, Ploss A, Lindenbach B. A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating. 2020, 147. DOI: 10.3390/proceedings2020050147.Peer-Reviewed Original Research
2016
Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia
Onorati M, Li Z, Liu F, Sousa AMM, Nakagawa N, Li M, Dell’Anno M, Gulden FO, Pochareddy S, Tebbenkamp AT, Han W, Pletikos M, Gao T, Zhu Y, Bichsel C, Varela L, Szigeti-Buck K, Lisgo S, Zhang Y, Testen A, Gao XB, Mlakar J, Popovic M, Flamand M, Strittmatter SM, Kaczmarek LK, Anton ES, Horvath TL, Lindenbach BD, Sestan N. Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Reports 2016, 16: 2576-2592. PMID: 27568284, PMCID: PMC5135012, DOI: 10.1016/j.celrep.2016.08.038.Peer-Reviewed Original ResearchMeSH KeywordsAxl Receptor Tyrosine KinaseBrainCell DeathCentrosomeFetusGene Expression ProfilingHumansImmunity, InnateMicrocephalyMitochondriaMitosisNeocortexNeural Stem CellsNeuroepithelial CellsNeurogliaNeuronsNeuroprotective AgentsNucleosidesPhosphorylationProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSpinal CordTranscription, GeneticVirus ReplicationZika VirusZika Virus InfectionConceptsRadial glial cellsNES cellsNeuroepithelial stem cellsZIKV infectionFetal brain slicesStem cellsEarly human neurodevelopmentHuman neuroepithelial stem cellsHuman neural stem cellsCell deathSingle-cell RNA-seqNeural stem cellsNeurodevelopment defectsZIKV replicationGlial cellsBrain slicesPotential treatmentRadial gliaZika virusPhospho-TBK1Neurodevelopmental defectsRNA-seqSupernumerary centrosomesNucleoside analoguesHuman neurodevelopmentVaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection
Yockey LJ, Varela L, Rakib T, Khoury-Hanold W, Fink SL, Stutz B, Szigeti-Buck K, Van den Pol A, Lindenbach BD, Horvath TL, Iwasaki A. Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection. Cell 2016, 166: 1247-1256.e4. PMID: 27565347, PMCID: PMC5006689, DOI: 10.1016/j.cell.2016.08.004.Peer-Reviewed Original ResearchMeSH KeywordsAbortion, HabitualAnimalsBrainBrain DiseasesDisease Models, AnimalFemaleFetal Growth RetardationInterferon Regulatory Factor-3MiceMice, Inbred C57BLMice, Mutant StrainsPregnancyPregnancy Complications, InfectiousReceptor, Interferon alpha-betaVaginaVirus ReplicationZika VirusZika Virus InfectionConceptsZika virusFetal brain infectionFetal growth restrictionLocal viral replicationWild-type miceType I interferon receptorZIKV challengeTranscription factor IRF3Vaginal exposureGenital mucosaBrain infectionWT miceEarly pregnancyZIKV infectionGrowth restrictionPregnant damsVaginal infectionsZIKV replicationFetal brainMouse modelIFN pathwayVaginal tractUnborn fetusViral replicationDisease consequencesThe Coding Region of the HCV Genome Contains a Network of Regulatory RNA Structures
Pirakitikulr N, Kohlway A, Lindenbach BD, Pyle AM. The Coding Region of the HCV Genome Contains a Network of Regulatory RNA Structures. Molecular Cell 2016, 62: 111-120. PMID: 26924328, PMCID: PMC4826301, DOI: 10.1016/j.molcel.2016.01.024.Peer-Reviewed Original ResearchConceptsRNA structureRegulatory RNA structuresComparative sequence analysisStructural RNA motifsRNA structure modelingLife cycleVirus life cycleRNA motifsPrimary sequenceCoding regionsGenomeBiological processesChemical probingSequence analysisRegulatory roleTertiary structureConformational changesVirus genomeFunctional assaysVersatile macromoleculesSpecific stagesStructure modelingFunctional informationMotifC virus genome
2015
Hepatitis C Virus RNA Replication Depends on Specific Cis- and Trans-Acting Activities of Viral Nonstructural Proteins
Kazakov T, Yang F, Ramanathan HN, Kohlway A, Diamond MS, Lindenbach BD. Hepatitis C Virus RNA Replication Depends on Specific Cis- and Trans-Acting Activities of Viral Nonstructural Proteins. PLOS Pathogens 2015, 11: e1004817. PMID: 25875808, PMCID: PMC4395149, DOI: 10.1371/journal.ppat.1004817.Peer-Reviewed Original ResearchConceptsRNA bindingRNA replicationPositive-strand RNA virus replicationComplementation group analysisPositive-strand RNA virusesPolymerase activityRNA virus replicationNS3 helicase domainViral nonstructural proteinsCis-acting roleGene functionVirus RNA replicationHelicase domainSpecific cisReplicase geneGenome replicationReplicase assemblyLethal mutationsNonstructural genesNTPase activityStudy of cisNonstructural proteinsRNA virusesSynthetic mRNAFunctional linkage
2013
Hepatitis C Virus RNA Replication and Virus Particle Assembly Require Specific Dimerization of the NS4A Protein Transmembrane Domain
Kohlway A, Pirakitikulr N, Barrera FN, Potapova O, Engelman DM, Pyle AM, Lindenbach BD. Hepatitis C Virus RNA Replication and Virus Particle Assembly Require Specific Dimerization of the NS4A Protein Transmembrane Domain. Journal Of Virology 2013, 88: 628-642. PMID: 24173222, PMCID: PMC3911751, DOI: 10.1128/jvi.02052-13.Peer-Reviewed Original ResearchConceptsTM domainVirus particle assemblyRNA replicationTransmembrane protein essentialProtein transmembrane domainProtein-protein interactionsProtein interaction systemForward geneticsVirus RNA replicationParticle assemblySpecific dimerizationTransmembrane domainHuman blood group antigensProtein essentialTM helicesMutational effectsHomotypic interactionsDimer interfacePotential dimerizationTM interactionsVirus assemblyNonstructural proteinsDimeric interactionsHepatitis C Virus RNA ReplicationMutationsThe ins and outs of hepatitis C virus entry and assembly
Lindenbach BD, Rice CM. The ins and outs of hepatitis C virus entry and assembly. Nature Reviews Microbiology 2013, 11: 688-700. PMID: 24018384, PMCID: PMC3897199, DOI: 10.1038/nrmicro3098.Peer-Reviewed Original ResearchConceptsHCV particlesRNA virusesPositive-strand RNA virusesSignal transduction eventsSerum lipoproteinsCell surface proteinsHepatitis C Virus EntryNumerous cell surface proteinsNon-structural proteinsNew structural informationC virus entrySecretory pathwayTransduction eventsUncharacterized mechanismMembrane fusionHCV particle assemblyCellular processingSurface proteinsC virus