2024
Intestinal tuft cell immune privilege enables norovirus persistence
Strine M, Fagerberg E, Darcy P, Barrón G, Filler R, Alfajaro M, D'Angelo-Gavrish N, Wang F, Graziano V, Menasché B, Damo M, Wang Y, Howitt M, Lee S, Joshi N, Mucida D, Wilen C. Intestinal tuft cell immune privilege enables norovirus persistence. Science Immunology 2024, 9: eadi7038. PMID: 38517952, DOI: 10.1126/sciimmunol.adi7038.Peer-Reviewed Original ResearchConceptsCD8<sup>+</sup> T cellsIntestinal tuft cellsT cellsTufted cellsViral persistenceSite of viral persistenceChemosensory epithelial cellsNormal antigen presentationImmune-privileged nicheIntestinal stem cellsMemory phenotypeImmune privilegeImmune escapeReporter miceAntigen presentationChronic infectionCytotoxic capacityEpithelial cellsNorovirus infectionStem cellsCell interactionsInfectionCell survivalEnteric microbesCellsHuman 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
IFN-λ derived from nonsusceptible enterocytes acts on tuft cells to limit persistent norovirus
Ingle H, Makimaa H, Aggarwal S, Deng H, Foster L, Li Y, Kennedy E, Peterson S, Wilen C, Lee S, Suthar M, Baldridge M. IFN-λ derived from nonsusceptible enterocytes acts on tuft cells to limit persistent norovirus. Science Advances 2023, 9: eadi2562. PMID: 37703370, PMCID: PMC10499323, DOI: 10.1126/sciadv.adi2562.Peer-Reviewed Original ResearchConceptsIntestinal epithelial cellsTuft cellsUninfected bystander cellsIFN-λ signalingSource of IFNImmune cellsIntestinal infectionsLeading causeViral gastroenteritisMNoVNorovirus pathogenesisCellular tropismPotent antiviralEpidemic viral gastroenteritisEpithelial cellsBystander cellsIFNNorovirusAntiviralsInfectionMurine norovirusIntercellular communicationPersistent strainsCellsVivoGame over for RSV?
Strine M, Wilen C. Game over for RSV? Science Immunology 2023, 8: eadi8764. PMID: 37276355, PMCID: PMC11528347, DOI: 10.1126/sciimmunol.adi8764.Commentaries, Editorials and Letters
2022
Tuft-cell-intrinsic and -extrinsic mediators of norovirus tropism regulate viral immunity
Strine M, Alfajaro M, Graziano V, Song J, Hsieh L, Hill R, Guo J, VanDussen K, Orchard R, Baldridge M, Lee S, Wilen C. Tuft-cell-intrinsic and -extrinsic mediators of norovirus tropism regulate viral immunity. Cell Reports 2022, 41: 111593. PMID: 36351394, PMCID: PMC9662704, DOI: 10.1016/j.celrep.2022.111593.Peer-Reviewed Original ResearchDe 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 benefitsMutationsIndolentHigh-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells
Chen JS, Chow RD, Song E, Mao T, Israelow B, Kamath K, Bozekowski J, Haynes WA, Filler RB, Menasche BL, Wei J, Alfajaro MM, Song W, Peng L, Carter L, Weinstein JS, Gowthaman U, Chen S, Craft J, Shon JC, Iwasaki A, Wilen CB, Eisenbarth SC. High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells. Science Immunology 2022, 7: eabl5652. PMID: 34914544, PMCID: PMC8977051, DOI: 10.1126/sciimmunol.abl5652.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionSARS-CoV-2Follicular helper cellsB cell responsesHelper cellsAntibody productionCell responsesSARS-CoV-2 vaccinationB-cell receptor sequencingSevere COVID-19Cell receptor sequencingIndependent antibodiesT cell-B cell interactionsViral inflammationAntiviral antibodiesImmunoglobulin class switchingVirus infectionGerminal centersViral infectionClonal repertoireInfectionAntibodiesClass switchingCOVID-19Patients
2021
Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy
Ullah I, Prévost J, Ladinsky MS, Stone H, Lu M, Anand SP, Beaudoin-Bussières G, Symmes K, Benlarbi M, Ding S, Gasser R, Fink C, Chen Y, Tauzin A, Goyette G, Bourassa C, Medjahed H, Mack M, Chung K, Wilen CB, Dekaban GA, Dikeakos JD, Bruce EA, Kaufmann DE, Stamatatos L, McGuire AT, Richard J, Pazgier M, Bjorkman PJ, Mothes W, Finzi A, Kumar P, Uchil PD. Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy. Immunity 2021, 54: 2143-2158.e15. PMID: 34453881, PMCID: PMC8372518, DOI: 10.1016/j.immuni.2021.08.015.Peer-Reviewed Original ResearchConceptsCOVID-19 convalescent subjectsSARS-CoV-2 infectionBioluminescence imagingK18-hACE2 miceLive bioluminescence imagingNatural killer cellsFc effector functionsSARS-CoV-2Convalescent subjectsKiller cellsPotent NAbsImmune protectionInflammatory responseEffector functionsNasal cavityNaB treatmentOptimal efficacyFc functionDepletion studiesMiceNAbsCOVID-19Direct neutralizationInfectionAntibodiesNeuroinvasion of SARS-CoV-2 in human and mouse brain
Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Ravindra NG, Van Dijk D, Mane S, Gunel M, Ring A, Kazmi SAJ, Zhang K, Wilen CB, Horvath TL, Plu I, Haik S, Thomas JL, Louvi A, Farhadian SF, Huttner A, Seilhean D, Renier N, Bilguvar K, Iwasaki A. Neuroinvasion of SARS-CoV-2 in human and mouse brain. Journal Of Experimental Medicine 2021, 218: e20202135. PMID: 33433624, PMCID: PMC7808299, DOI: 10.1084/jem.20202135.Peer-Reviewed Original ResearchConceptsSARS-CoV-2Central nervous systemSARS-CoV-2 neuroinvasionImmune cell infiltratesCOVID-19 patientsType I interferon responseMultiple organ systemsCOVID-19I interferon responseHuman brain organoidsNeuroinvasive capacityCNS infectionsCell infiltrateNeuronal infectionPathological featuresCortical neuronsRespiratory diseaseDirect infectionCerebrospinal fluidNervous systemMouse brainInterferon responseOrgan systemsHuman ACE2Infection
2020
Cytidine Monophosphate N-Acetylneuraminic Acid Synthetase and Solute Carrier Family 35 Member A1 Are Required for Reovirus Binding and Infection
Urbanek K, Sutherland DM, Orchard RC, Wilen CB, Knowlton JJ, Aravamudhan P, Taylor GM, Virgin HW, Dermody TS. Cytidine Monophosphate N-Acetylneuraminic Acid Synthetase and Solute Carrier Family 35 Member A1 Are Required for Reovirus Binding and Infection. Journal Of Virology 2020, 95: 10.1128/jvi.01571-20. PMID: 33087464, PMCID: PMC7944449, DOI: 10.1128/jvi.01571-20.Peer-Reviewed Original ResearchConceptsSialic acid expressionMicroglial cellsCell surface expressionReovirus-induced cell deathReovirus infectionSialic acidMurine microglial BV2 cellsReovirus-induced diseaseMember A1Microglial BV2 cellsSurface expressionMurine microglial cellsCell deathReovirus bindingBV2 cellsViral tropismInfectionHost genesLow-level bindingCell surface receptorsHost factorsCell surfaceReceptorsSialic acid synthesisSurface receptorsCD300lf is the primary physiologic receptor of murine norovirus but not human norovirus
Graziano VR, Walker FC, Kennedy EA, Wei J, Ettayebi K, Strine MS, Filler RB, Hassan E, Hsieh LL, Kim AS, Kolawole AO, Wobus CE, Lindesmith LC, Baric RS, Estes MK, Orchard RC, Baldridge MT, Wilen CB. CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus. PLOS Pathogens 2020, 16: e1008242. PMID: 32251490, PMCID: PMC7162533, DOI: 10.1371/journal.ppat.1008242.Peer-Reviewed Original ResearchConceptsMNoV infectionPrimary physiologic receptorPhysiologic receptorHuman norovirusMurine norovirusBona fide receptorHumoral responseVirus infectionEntry receptorReceptor utilizationCell tropismInfectionReceptorsVirus-like particlesFide receptorCD300lfNorovirusHNoVCD300ldMajor determinantProteinaceous receptorsVivoMNoV.MNoVPathogenesis
2019
The intestinal regionalization of acute norovirus infection is regulated by the microbiota via bile acid-mediated priming of type III interferon
Grau KR, Zhu S, Peterson ST, Helm EW, Philip D, Phillips M, Hernandez A, Turula H, Frasse P, Graziano VR, Wilen CB, Wobus CE, Baldridge MT, Karst SM. The intestinal regionalization of acute norovirus infection is regulated by the microbiota via bile acid-mediated priming of type III interferon. Nature Microbiology 2019, 5: 84-92. PMID: 31768030, PMCID: PMC6925324, DOI: 10.1038/s41564-019-0602-7.Peer-Reviewed Original ResearchConceptsNorovirus infectionType III interferonsMurine norovirus infectionCommensal bacteriaIII interferonsIntestinal microbiotaType III interferon responseBile acid receptorProximal small intestineRegional expression profilesProximal gutAntibiotic treatmentViral infectionSmall intestineIntestinal tractAcid receptorsInfectionInterferon responseMicrobiotaInterferonPathogenic enteric virusesEnteric virusesHost metabolitesGutExpression profilesA Secreted Viral Nonstructural Protein Determines Intestinal Norovirus Pathogenesis
Lee S, Liu H, Wilen CB, Sychev ZE, Desai C, Hykes BL, Orchard RC, McCune BT, Kim KW, Nice TJ, Handley SA, Baldridge MT, Amarasinghe GK, Virgin HW. A Secreted Viral Nonstructural Protein Determines Intestinal Norovirus Pathogenesis. Cell Host & Microbe 2019, 25: 845-857.e5. PMID: 31130511, PMCID: PMC6622463, DOI: 10.1016/j.chom.2019.04.005.Peer-Reviewed Original ResearchConceptsNS1 secretionTuft cellsIFN-λ responseAnti-capsid antibodiesMNoV infectionAcute infectionIntestinal infectionsLack of inductionPersistent infectionNorovirus pathogenesisCaspase-3 cleavageIFN responseInfectionSecretionViral nonstructural proteinsIFNProtein 1/2Viral proteinsMurine norovirusNS1Lower percentageNonstructural proteinsCellsLow numberVaccination
2018
Tropism for tuft cells determines immune promotion of norovirus pathogenesis
Wilen CB, Lee S, Hsieh LL, Orchard RC, Desai C, Hykes BL, McAllaster MR, Balce DR, Feehley T, Brestoff JR, Hickey CA, Yokoyama CC, Wang YT, MacDuff DA, Kreamalmayer D, Howitt MR, Neil JA, Cadwell K, Allen PM, Handley SA, van Lookeren Campagne M, Baldridge MT, Virgin HW. Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science 2018, 360: 204-208. PMID: 29650672, PMCID: PMC6039974, DOI: 10.1126/science.aar3799.Peer-Reviewed Original ResearchConceptsVirus infectionImmune promotionTuft cellsType 2 cytokinesEnteric virus infectionEnteric viral infectionsIntestinal epithelial cellsMNoV infectionNorovirus infectionCommensal microbiotaHost immunityViral infectionNorovirus pathogenesisRare typeImmune systemCellular tropismInfectionMouse intestineTarget cellsEpithelial cellsCell proliferationCytokinesTropismCD300lfCells
2017
Norovirus Cell Tropism Is Determined by Combinatorial Action of a Viral Non-structural Protein and Host Cytokine
Lee S, Wilen CB, Orvedahl A, McCune BT, Kim KW, Orchard RC, Peterson ST, Nice TJ, Baldridge MT, Virgin HW. Norovirus Cell Tropism Is Determined by Combinatorial Action of a Viral Non-structural Protein and Host Cytokine. Cell Host & Microbe 2017, 22: 449-459.e4. PMID: 28966054, PMCID: PMC5679710, DOI: 10.1016/j.chom.2017.08.021.Peer-Reviewed Original ResearchConceptsIntestinal epithelial cellsViral surface proteinsCellular tropismPersistent viral infectionNon-structural protein NS1Expression of NS1MNoV infectionSurface proteinsHost cytokinesAntiviral immunityHost determinantsInterferon lambdaViral infectionKey host determinantsViral non-structural proteinsCell tropismFecal sheddingNon-structural proteinsTropism determinantsEpithelial cellsGlobal causeInfectionTropismProtein NS1MNoVEpidemiology of Bloodstream Infections
McMullen A, Wilen C, Burnham C. Epidemiology of Bloodstream Infections. 2017, 163-181. DOI: 10.1128/9781555819811.ch9.Peer-Reviewed Original ResearchHematopoietic stem cell transplantationSolid organ transplantationBloodstream infectionsStem cell transplantationPositive blood culturesHealth care settingsImmunosuppressive regimensClinical microbiology laboratoryCell transplantationBlood culturesOrgan transplantationCare settingsInvasive proceduresPractice changeMicrobiology laboratoryEpidemiologyInfectionAntimicrobial resistanceHealth careTransplantationNumber of advancesRegimensSettingCare
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 structureResiduesAltered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome
Monaco CL, Gootenberg DB, Zhao G, Handley SA, Ghebremichael MS, Lim ES, Lankowski A, Baldridge MT, Wilen CB, Flagg M, Norman JM, Keller BC, Luévano JM, Wang D, Boum Y, Martin JN, Hunt PW, Bangsberg DR, Siedner MJ, Kwon DS, Virgin HW. Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome. Cell Host & Microbe 2016, 19: 311-322. PMID: 26962942, PMCID: PMC4821831, DOI: 10.1016/j.chom.2016.02.011.Peer-Reviewed Original ResearchConceptsAnti-retroviral therapyEnteric viromePeripheral CD4 T-cell countLower CD4 T countsCD4 T-cell countHuman immunodeficiency virus (HIV) infectionProgressive HIV infectionT-cell countsImmunodeficiency virus infectionAcquired Immunodeficiency SyndromeHIV-uninfectedUgandan patientsHIV infectionImmunodeficiency syndromeIntestinal translocationDisease progressionVirus infectionART treatmentBacterial microbiomeCell countInfectionGut bacterial communitiesPatientsImmunodeficiencySpecific bacteria
2015
Markers of Intestinal Inflammation for the Diagnosis of Infectious Gastroenteritis
Gonzalez MD, Wilen CB, Burnham CA. Markers of Intestinal Inflammation for the Diagnosis of Infectious Gastroenteritis. Clinics In Laboratory Medicine 2015, 35: 333-344. PMID: 26004646, DOI: 10.1016/j.cll.2015.02.001.Peer-Reviewed Original ResearchConceptsInfectious gastroenteritisIntestinal inflammationSystemic biomarkersInfectious diarrheaInvasive testingFecal biomarkersParasitic infectionsHost responseMajor causeGastroenteritisDiagnosisAdjunct diagnosticsStand-alone testsBiomarkersAssaysInexpensive assayMorbidityDiarrheaInflammationTherapyInfection
2013
Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection
Didigu CA, Wilen CB, Wang J, Duong J, Secreto AJ, Danet-Desnoyers GA, Riley JL, Gregory PD, June CH, Holmes MC, Doms RW. Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection. Blood 2013, 123: 61-69. PMID: 24162716, PMCID: PMC3879906, DOI: 10.1182/blood-2013-08-521229.Peer-Reviewed Original ResearchConceptsC chemokine receptor 5HIV-1 infectionT cellsHIV-1HIV coreceptor CCR5Chemokine receptor 5Humanized mouse modelDrug-free treatmentHIV-1 entryHIV coreceptorsPharmacologic blockadeCoreceptor CCR5Mouse modelCells engraftReceptor 5Gene-modified cellsCXCR4InfectionPrimary humanCoreceptorCD4CCR5Genetic inactivationVirusCells