2023
PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
Xu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 2023, 619: 819-827. PMID: 37438530, PMCID: PMC10371867, DOI: 10.1038/s41586-023-06322-y.Peer-Reviewed Original ResearchConceptsC-terminal β-barrel domainSpike-mediated fusionCell-autonomous defenseLarge-scale exome sequencingΒ-barrel domainGenome-wide CRISPRSARS-CoV-2 infectionHost cell cytosolScramblase activityPhospholipid scramblaseLive SARS-CoV-2 infectionHuman lung epitheliumPLSCR1SARS-CoV-2 USASingle-molecule switchingSARS-CoV-2 variantsExome sequencingHuman populationRestriction factorsViral RNANew SARS-CoV-2 variantsSARS-CoV-2Robust activityLung epitheliumDefense factorsDYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner
Strine M, Cai W, Wei J, Alfajaro M, Filler R, Biering S, Sarnik S, Chow R, Patil A, Cervantes K, Collings C, DeWeirdt P, Hanna R, Schofield K, Hulme C, Konermann S, Doench J, Hsu P, Kadoch C, Yan Q, Wilen C. DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner. PLOS Biology 2023, 21: e3002097. PMID: 37310920, PMCID: PMC10263356, DOI: 10.1371/journal.pbio.3002097.Peer-Reviewed Original ResearchConceptsGenome-wide CRISPR/Cas9 screenCRISPR/Cas9 screenPathogenic human coronavirusesKinase-independent mannerRegulated kinase 1AProviral host factorNovel drug targetsMultiple cell typesDNA accessibilityHost factorsKinase functionHuman coronavirusesHost genesDistal enhancerNovel regulatorCas9 screenKinase 1AGene expressionNeuronal developmentDYRK1ADrug targetsDiverse coronavirusesProviral activityCell typesSevere acute respiratory syndrome coronavirus 2
2020
An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2
Tada T, Fan C, Chen JS, Kaur R, Stapleford KA, Gristick H, Dcosta BM, Wilen CB, Nimigean CM, Landau NR. An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2. Cell Reports 2020, 33: 108528. PMID: 33326798, PMCID: PMC7705358, DOI: 10.1016/j.celrep.2020.108528.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAngiotensin-Converting Enzyme 2AnimalsAntiviral AgentsCOVID-19Disease Models, AnimalDisulfidesFemaleHEK293 CellsHumansImmunoglobulin Fc FragmentsMaleMice, TransgenicMicrobodiesProtein DomainsProtein MultimerizationSARS-CoV-2Spike Glycoprotein, CoronavirusVirionVirus InternalizationConceptsSARS-CoV-2Soluble ACE2Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionAcute respiratory syndrome coronavirus 2 infectionLive SARS-CoV-2Syndrome coronavirus 2 infectionCoronavirus 2 infectionSARS-CoV-2 spikeCoronavirus disease 2019SARS-CoV-2 spike proteinDisease 2019Enzyme 2Mouse modelFuture coronavirusesFc fusion proteinΒ-coronavirusViral variantsImmunoglobulin heavy chainSpike proteinACE2 ectodomainImmunoglobulin Fc domainFc domainVirusACE2Potent inhibitorGenome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection
Wei J, Alfajaro MM, DeWeirdt PC, Hanna RE, Lu-Culligan WJ, Cai WL, Strine MS, Zhang SM, Graziano VR, Schmitz CO, Chen JS, Mankowski MC, Filler RB, Ravindra NG, Gasque V, de Miguel FJ, Patil A, Chen H, Oguntuyo KY, Abriola L, Surovtseva YV, Orchard RC, Lee B, Lindenbach BD, Politi K, van Dijk D, Kadoch C, Simon MD, Yan Q, Doench JG, Wilen CB. Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection. Cell 2020, 184: 76-91.e13. PMID: 33147444, PMCID: PMC7574718, DOI: 10.1016/j.cell.2020.10.028.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2AnimalsCell LineChlorocebus aethiopsClustered Regularly Interspaced Short Palindromic RepeatsCoronavirusCoronavirus InfectionsCOVID-19Gene Knockout TechniquesGene Regulatory NetworksGenome-Wide Association StudyHEK293 CellsHMGB1 ProteinHost-Pathogen InteractionsHumansSARS-CoV-2Vero CellsVirus InternalizationConceptsSARS-CoV-2 infectionSARS-CoV-2Vesicular stomatitis virusGenome-wide CRISPR screenSWI/SNF chromatinSARS-CoV-2 host factorsAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionTherapeutic targetHost factorsCoronavirus disease 2019 (COVID-19) pathogenesisSyndrome coronavirus 2 infectionCRISPR screensHost genesGene productsMiddle East respiratory syndrome CoVCoronavirus 2 infectionGenetic hitsHuman cellsSARS-CoV-2 spikeNovel therapeutic targetPotential therapeutic targetVero E6 cellsSARS-CoV-1Small molecule antagonistsCD300LF Polymorphisms of Inbred Mouse Strains Confer Resistance to Murine Norovirus Infection in a Cell Type-Dependent Manner
Furlong K, Biering SB, Choi J, Wilen CB, Orchard RC, Wobus CE, Nelson CA, Fremont DH, Baldridge MT, Randall G, Hwang S. CD300LF Polymorphisms of Inbred Mouse Strains Confer Resistance to Murine Norovirus Infection in a Cell Type-Dependent Manner. Journal Of Virology 2020, 94: 10.1128/jvi.00837-20. PMID: 32581099, PMCID: PMC7431780, DOI: 10.1128/jvi.00837-20.Peer-Reviewed Original ResearchConceptsBone marrow-derived macrophagesCell type-dependent mannerType-dependent mannerCell typesMacrophage-like cellsRobust experimental systemMNV infectionRelated murine norovirusSpecific cell typesCorresponding mutantsMarrow-derived macrophagesMurine norovirus infectionEntry factorsMurine norovirusCD300lfCause of gastroenteritisNonpermissive cellsProteinaceous receptorsConfer resistanceHuman cellsHost cellsDifferent allelesAmino acidsC57BL/6J allelePermissive cells
2019
Norovirus Attachment and Entry
Graziano VR, Wei J, Wilen CB. Norovirus Attachment and Entry. Viruses 2019, 11: 495. PMID: 31151248, PMCID: PMC6630345, DOI: 10.3390/v11060495.Peer-Reviewed Original ResearchConceptsHisto-blood group antigensNorovirus attachmentMajority of casesMajor human pathogenViral life cycleImmune interactionsViral gastroenteritisCell tropismGroup antigensViral entryKey mediatorHuman norovirusBile saltsViral genome releaseMurine norovirusReceptorsMinor capsid protein VP2Capsid protein VP2Human pathogensMolecular mechanismsNorovirusSignificant determinantsProtein VP2Important future directionsCurrent understanding
2016
Discovery of a proteinaceous cellular receptor for a norovirus
Orchard RC, Wilen CB, Doench JG, Baldridge MT, McCune BT, Lee YC, Lee S, Pruett-Miller SM, Nelson CA, Fremont DH, Virgin HW. Discovery of a proteinaceous cellular receptor for a norovirus. Science 2016, 353: 933-936. PMID: 27540007, PMCID: PMC5484048, DOI: 10.1126/science.aaf1220.Peer-Reviewed Original ResearchConceptsProteinaceous receptorsMNoV infectionCellular machineryNoV replicationHuman cellsCell deathSpecies barrierCD300lfSpecies tropismPrimary cellsCellular receptorsCell linesMurine NoVHost factorsReplicationCause of gastroenteritisPrimary determinantNoV infectionReceptorsCellsEctodomainMachineryInfectionCrystal structureResidues
2014
The Major Cellular Sterol Regulatory Pathway Is Required for Andes Virus Infection
Petersen J, Drake MJ, Bruce EA, Riblett AM, Didigu CA, Wilen CB, Malani N, Male F, Lee FH, Bushman FD, Cherry S, Doms RW, Bates P, Briley K. The Major Cellular Sterol Regulatory Pathway Is Required for Andes Virus Infection. PLOS Pathogens 2014, 10: e1003911. PMID: 24516383, PMCID: PMC3916400, DOI: 10.1371/journal.ppat.1003911.Peer-Reviewed Original ResearchConceptsRegulatory pathwaysHuman haploid cellsParallel genetic screensGenetic screenPathogenic New World hantavirusesGenomic screenAndes virusHaploid cellsGene disruptionRNA interferenceANDV entryDeficient cellsCellular requirementsCellular cholesterolRNA virusesANDV infectionLarge familyPharmacologic inhibitionWorldwide distributionAndes Virus InfectionNew World hantavirusesVirus bindingPathwayHost factorsSterol synthesis
2012
Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5
Parker ZF, Iyer SS, Wilen CB, Parrish NF, Chikere KC, Lee FH, Didigu CA, Berro R, Klasse PJ, Lee B, Moore JP, Shaw GM, Hahn BH, Doms RW. Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5. Journal Of Virology 2012, 87: 2401-2411. PMID: 23269796, PMCID: PMC3571396, DOI: 10.1128/jvi.02964-12.Peer-Reviewed Original ResearchConceptsCCR5 expression levelsF EnvsTransmitted/FounderHIV-1 envelope proteinCCR5 antagonist maravirocSingle genome amplificationExpression levelsSingle virus variantReplication-competent virusMVC resistanceFounder virusesChronic infectionCCR5 antagonistsT cellsHIV-1CCR5MaravirocControl virusPhysiologic levelsCCR5 conformationsVirus variantsEnvelope glycoproteinEnv proteinEnvInfectionTransmitted/Founder and Chronic Subtype C HIV-1 Use CD4 and CCR5 Receptors with Equal Efficiency and Are Not Inhibited by Blocking the Integrin α4β7
Parrish NF, Wilen CB, Banks LB, Iyer SS, Pfaff JM, Salazar-Gonzalez JF, Salazar MG, Decker JM, Parrish EH, Berg A, Hopper J, Hora B, Kumar A, Mahlokozera T, Yuan S, Coleman C, Vermeulen M, Ding H, Ochsenbauer C, Tilton JC, Permar SR, Kappes JC, Betts MR, Busch MP, Gao F, Montefiori D, Haynes BF, Shaw GM, Hahn BH, Doms RW. Transmitted/Founder and Chronic Subtype C HIV-1 Use CD4 and CCR5 Receptors with Equal Efficiency and Are Not Inhibited by Blocking the Integrin α4β7. PLOS Pathogens 2012, 8: e1002686. PMID: 22693444, PMCID: PMC3364951, DOI: 10.1371/journal.ppat.1002686.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, NeutralizingAntibodies, ViralCD4 AntigensCD4-Positive T-LymphocytesCells, CulturedCloning, MolecularHIV Envelope Protein gp120HIV InfectionsHIV-1Host-Pathogen InteractionsHumansIntegrinsMucous MembraneNeutralization TestsReceptors, CCR5Viral TropismVirus InternalizationVirus ReplicationConceptsF virusesInfectious molecular cloneMucosal HIV-1 acquisitionNew HIV-1 infectionsHuman immunodeficiency virus type 1Immunodeficiency virus type 1Transmitted/FounderHIV-1 acquisitionHIV-1 vaccine designSubtype C HIVHIV-1 infectionSingle genome amplificationAnti-α4β7 antibodyVirus type 1V2 variable loopsChronic EnvsC HIVFounder virusesSexual transmissionChronic virusesGp120 subunitIntegrin α4β7Transmission fitnessSame CD4CD4
2011
Molecular Mechanisms of HIV Entry
Wilen CB, Tilton JC, Doms RW. Molecular Mechanisms of HIV Entry. Advances In Experimental Medicine And Biology 2011, 726: 223-242. PMID: 22297516, DOI: 10.1007/978-1-4614-0980-9_10.Peer-Reviewed Original ResearchConceptsHIV entryOnly viral surface proteinHuman immunodeficiency virus (HIV) entryHumoral immune responseMembrane fusion machineryCoreceptor-binding siteHost protein CD4Viral surface proteinsHIV infectionSmall molecule inhibitorsImmune responseChemokine coreceptorsFusion machineryViral tropismClinical treatmentVirus entryMolecular mechanismsHost cellsFacilitates exposureMolecule inhibitorsGp41 subunitSurface proteinsViral genomeAmino acidsCD4Phenotypic and Immunologic Comparison of Clade B Transmitted/Founder and Chronic HIV-1 Envelope Glycoproteins
Wilen CB, Parrish NF, Pfaff JM, Decker JM, Henning EA, Haim H, Petersen JE, Wojcechowskyj JA, Sodroski J, Haynes BF, Montefiori DC, Tilton JC, Shaw GM, Hahn BH, Doms RW. Phenotypic and Immunologic Comparison of Clade B Transmitted/Founder and Chronic HIV-1 Envelope Glycoproteins. Journal Of Virology 2011, 85: 8514-8527. PMID: 21715507, PMCID: PMC3165820, DOI: 10.1128/jvi.00736-11.Peer-Reviewed Original ResearchConceptsMucosal barrierF EnvsNeutralization sensitivitySingle-round infectivity assaysHuman immunodeficiency virus type 1Immunodeficiency virus type 1Enhanced neutralization sensitivityTransmitted/FounderHIV-1 envelope glycoproteinHIV-1 transmissionIntact mucosal barrierClade B EnvVirus type 1Chronic EnvsHIV-IgDendritic cellsCoreceptor tropismFounder virusesSexual transmissionEnv phenotypeAntibody b12Chronic controlEffective vaccineNew infectionsEnv trimersEngineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases
Wilen CB, Wang J, Tilton JC, Miller JC, Kim KA, Rebar EJ, Sherrill-Mix SA, Patro SC, Secreto AJ, Jordan AP, Lee G, Kahn J, Aye PP, Bunnell BA, Lackner AA, Hoxie JA, Danet-Desnoyers GA, Bushman FD, Riley JL, Gregory PD, June CH, Holmes MC, Doms RW. Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases. PLOS Pathogens 2011, 7: e1002020. PMID: 21533216, PMCID: PMC3077364, DOI: 10.1371/journal.ppat.1002020.Peer-Reviewed Original ResearchConceptsT cellsHIV-1Human CD4X4-tropic HIV-1X4 HIV-1CCR5-tropic virusHumanized mouse modelLoss of CXCR4CXCR4-tropic HIVHIV-1 entryHuman T cellsCCR5Δ32 polymorphismAdoptive transferAutologous transplantCell surface expressionCXCR4 coreceptorMouse modelCD4CCR5CXCR4Surface expressionHIVInfectionSuch cellsHost cells