Brett Lindenbach, PhD
Associate Professor of Microbial Pathogenesis and of Comparative MedicineCards
Appointments
Contact Info
Microbial Pathogenesis
Department of Microbial Pathogenesis, 295 Congress Ave
New Haven, CT 06536-0812
United States
About
Titles
Associate Professor of Microbial Pathogenesis and of Comparative Medicine
Biography
In Memoriam
1968–2023
Brett Lindenbach, PhD, associate professor of microbial pathogenesis and of comparative medicine at Yale School of Medicine, died on December 16, 2023. He was 55. He had endured glioblastoma and its treatments (both standard and investigational) for 20 months.
Lindenbach grew up in the Chicago area and completed his undergraduate studies at the University of Illinois Urbana-Champaign. After earning his PhD in immunology at Washington University in St. Louis, he conducted postdoctoral research at the University of Wisconsin-Madison and the Rockefeller University. Working with Charles Rice, PhD, Lindenbach developed the first robust cell culture model of the hepatitis C virus (HCV). This advance and its accompanying insights led to the powerful new antiviral drugs that are now used to cure this virus. In 2006, he joined the Department of Microbial Pathogenesis at Yale School of Medicine. His work has illuminated host and viral factors that promote HCV infection and has provided fundamental insights into the pathogenicity of diverse flaviviruses including Zika, and coronaviruses such as SARS-CoV2. In addition to his research accomplishments, he wrote the most extensive and high-impact reviews and books on RNA viruses and was a dedicated and talented teacher.
He collaborated extensively and generously with his colleagues at Yale. For example, he continued his studies on HCV together with colleagues in Molecular, Cellular & Developmental Biology and Molecular Biophysics & Biochemistry, elucidating structures and mechanisms of the machinery that replicates HCV and related viruses. He was a lead contributor of a consortium with investigators from the departments of Comparative Medicine (where he held secondary appointment), Neuroscience, Immunobiology, and Obstetrics, Gynecology & Reproductive Sciences during the 2016 Zika virus crisis, which delivered several key publications with immediate translational relevance. He continued his crucial input to collaborative studies during the COVID pandemic to better understand fundamental principles of SARS-CoV-2 infection from the start of the pandemic. He worked closely with colleagues at Yale from both clinical (Internal Medicine, Laboratory Medicine, Pathology), basic science departments (Immunobiology, Comparative Medicine, Molecular, Cellular & Developmental Biology), and the School of Public Health. His selfless teamwork in these endeavors to promote discoveries that solve critical health issues will be part of his legacy as a great scientist and as a companionate human being. Colleagues celebrate Lindenbach's contributions to fostering a growing virology research community at Yale and remember him as an inspiring teacher, mentor, and colleague.
Lindenbach is survived by his wife, Joanna Bloom, his daughters, Molly and Claire, his mother, Laurel Lindenbach, and his sisters, Kristen Diamond, Lauren Lindenbach, and Lindsay Lindenbach. He was a recipient of the Connecticut Brain Tumor Alliance’s June Rice Courage Award in 2022, and demonstrated true courage in facing the challenges of brain cancer.
Appointments
Microbial Pathogenesis
Associate Professor TenurePrimaryComparative Medicine
Associate Professor on TermSecondary
Other Departments & Organizations
Education & Training
- Research Associate
- The Rockefeller University (2006)
- Postdoctoral Fellow
- HHMI/University of Wisconsin (2002)
- PhD
- Washington University School of Medicine, Immunology (1999)
- BS
- University of Illinois, Biology (1990)
Research
Overview
Many RNA viruses encode RNA helicases that are essential for viral replication, and it is frequently assumed that these enzymes unwind double-stranded forms of the viral gemone. Indeed, many of these enzymes have been shown to have RNA binding, ATPase, and RNA unwinding activities in vitro. However, to date there is no direct evidence that these enzymes bind to or unwind viral RNA in infected cells. We recently identified several important activities of the HCV NS3-4A RNA helicase domain in recruiting RNA an template for replication and in in virus assembly.
RNA replication
For many HCV nonstructural (NS) proteins, biochemical activities have been characterized and several high-resolution crystal structures are available. However what we most lack is an understanding of how these pieces work together to form the active replication complex, and how host cofactors influence the steps of translation and replication. We are combining genetic and biochemical approaches to close this gap in our knowledge. Specifically, we have developed a novel trans-complementation system to dissect the features of viral NS proteins proteins required for assembly of functional replication complexes. By using this system, we discovered the HCV NS3-4A helicase recruits the viral genome in cis (i.e., the same RNA from which it is translated) out of translation and into RNA replication. We also found that NS5B has an essential cis-acting role in RNA replication, independent of its RNA binding and RNA polymerase activities. A comprehensive complementation group analysis revealed functional linkages between NS3-4A and NS4B and between NS5B and the upstream NS3-5A genes. Finally, NS5B polymerase activity segregated with a daclatasvir-sensitive NS5A activity, which could explain the synergy of this antiviral compound with nucleoside analogs in patients. Together, these studies define several new aspects of HCV replicase structure-function, help to explain the potency of HCV-specific combination therapies, and provide an experimental framework for the study of cis- and trans-acting activities in positive-strand RNA virus replication more generally.
Virus assembly
We discovered that the HCV NS2 protein interacts with both the viral E1-E2 glycoprotein complex and the NS3-4A enzyme complex and that these interactions are essential for virus particle assembly. To examine the cell biology of HCV particle assembly in greater detail, we developed methods to fluorescently label functional core protein in virus-producing cells. Our data revealed that core protein is rapidly trafficked to the surface of lipid droplets, which associate with the sites of virus assembly at the ER. After egress from lipid droplets, core protein is incorporated into virus particles, which bud into the ER and traffic via the secretory pathway. By examining core trafficking in NS2 mutants with or without second-site genetic suppressors in NS3, we showed that the interaction between NS2 and NS3-4A is essential for recruiting core from the surface of lipid droplets into virus particles. Our current working model is that the interaction between NS2 and NS3-4A regulates the flow of RNA out of replication and into packaging. Because RNA helicase activity is essential for RNA replication, which is a pre-requisite for virus assembly, we have developed a unqiue genetic approach to separate the functions of the NS3 helicase in viral genome replication from its role in virus assembly.
Bacterial effectors as probes to study (+) RNA virus-host cell biology
The mechanisms by which viruses interact with their host cells are incompletely understood; identifying these interactions remains a fundamentally important area of basic virus research. The three most common approaches to discovering virus-host cell interaction have been: 1) Genome-wide RNAi screens for host genes that influence viral replication; 2) Identifying protein-protein interactions via proteomics or genetic two-hybrid screens; 3) Screening pharmacological agents to disrupt known cellular pathways. While these approaches have been incredibly useful, their limitations include: variability in RNAi knockdown efficiency, off-target effects, limited reproducibility between genome-wide screens, false-positive scoring of protein-protein interactions, and a relatively small and nonspecific pharmacopeia. We are exploring a new strategy to identify virus-host cell interaction by employing a large collection of bacterial effector proteins as a genetic toolkit to surgically manipulate key cellular pathways. Many bacterial pathogens infect and survive within eukaryotic cells by injecting minute quantities of bacterial effector proteins, typically enzymes, into the cytosol of their hosts. These effector proteins have evolved to manipulate cellular pathways, prevent bacterial degradation, and favor bacterial replication. For instance, Legionella pneumophila, the causative agent of Legionnaire’s disease, synthesizes >300 effector proteins, some of which reprogram endolysosomal membrane trafficking, potently inhibit cellular autophagy, and divert innate immune responses. Importantly, many effector proteins retain their function when ectopically expressed in mammalian cells and can be used to study cellular pathways independent of bacterial infection. Bacterial effector proteins frequently target the same cellular pathways used by (+) RNA viruses. For instance, Legionella effector proteins manipulate Rab1, a key organizer of ER-to- Golgi membrane traffic and a host factor required for hepatitis C virus (HCV) replication. Other effectors inhibit autophagy, a pathway exploited by HCV and many other (+) RNA viruses. Based on these known functional overlaps we hypothesize that bacterial effector proteins can be used as tools to identify cellular pathways used by (+) RNA viruses.
Medical Research Interests
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Akiko Iwasaki, PhD
Anna Marie Pyle, PhD
Craig B. Wilen, MD, PhD
Maya Deshmukh
Mia Madel Alfajaro, DVM, PhD, MS
Tamas Horvath, DVM, PhD
Hepatitis C
Publications
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.ChaptersCitationsAltmetric
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 ResearchAltmetricConceptsBat 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsDirect-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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsTransient 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 ResearchCitationsAltmetric
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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsAstrovirus 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsSecondary 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsSARS-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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsZika 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 ResearchCitationsAltmetric
Academic Achievements & Community Involvement
activity American Society for Virology
Professional OrganizationsMemberDetails1997 - Presentactivity American Society for Microbiology
Professional OrganizationsMemberDetails2007 - Presentactivity NIH/NIAID
Peer Review Groups and Grant Study SectionsRepresentativeDetails2009 - Presentactivity American Association for the Study of Liver Disease
Professional OrganizationsMemberDetails2012 - Presentactivity American Society of Cell Biology
Professional OrganizationsMemberDetails01/02/2012 - Present
News & Links
Media
News
- December 20, 2023
In Memoriam: Brett Lindenbach, PhD
- October 17, 2023
The Brett Lindenbach Virology Fund
- July 01, 2020
COVID-related Pilot Projects Are Selected for Research Funding
- April 09, 2020
At Dean's Virtual Workshop, Yale Scientists Describe Their Work to Halt COVID-19 Pandemic
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Contacts
Microbial Pathogenesis
Department of Microbial Pathogenesis, 295 Congress Ave
New Haven, CT 06536-0812
United States