2018
Small Interfering RNA-Mediated Control of Virus Replication in the CNS Is Therapeutic and Enables Natural Immunity to West Nile Virus
Beloor J, Maes N, Ullah I, Uchil P, Jackson A, Fikrig E, Lee SK, Kumar P. Small Interfering RNA-Mediated Control of Virus Replication in the CNS Is Therapeutic and Enables Natural Immunity to West Nile Virus. Cell Host & Microbe 2018, 23: 549-556.e3. PMID: 29606496, PMCID: PMC6074029, DOI: 10.1016/j.chom.2018.03.001.Peer-Reviewed Original ResearchConceptsWest Nile virusWNV infectionCell-mediated immune responsesLate-stage therapySubsequent WNV infectionWNV-infected miceLong-term immunityNile virusWNV E proteinViral burdenIntranasal routeVirus clearanceVirus infectionImmune responseMice succumbPeripheral tissuesNatural immunitySurvival rateDisease resultsDay 9Virus replicationInfectionImmunityCNSVirus
2017
An essential role of PI3K in the control of West Nile virus infection
Wang L, Yang L, Fikrig E, Wang P. An essential role of PI3K in the control of West Nile virus infection. Scientific Reports 2017, 7: 3724. PMID: 28623344, PMCID: PMC5473900, DOI: 10.1038/s41598-017-03912-5.Peer-Reviewed Original ResearchConceptsWest Nile virus infectionPI3K inhibitorsPI3KVirus infectionImmune responseK inhibitorsType I IFN responseAntiviral immune responseI IFN responseCatalytic subunit p110δTNF-α protein productionPrimary mouse macrophagesFlaviviral infectionsAntiviral immunityIFN responseViral titersClass I PI3KAntiviral roleMRNA expressionPI3K activityIFNProtein expressionInfectionMouse macrophagesCell proliferation
2016
Interleukin-17A Promotes CD8+ T Cell Cytotoxicity To Facilitate West Nile Virus Clearance
Acharya D, Wang P, Paul AM, Dai J, Gate D, Lowery JE, Stokic DS, Leis AA, Flavell RA, Town T, Fikrig E, Bai F. Interleukin-17A Promotes CD8+ T Cell Cytotoxicity To Facilitate West Nile Virus Clearance. Journal Of Virology 2016, 91: 10.1128/jvi.01529-16. PMID: 27795421, PMCID: PMC5165211, DOI: 10.1128/jvi.01529-16.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCytotoxicity, ImmunologicFemaleGene ExpressionHumansInterleukin-17MiceMice, Inbred C57BLNeuronsPrimary Cell CultureReceptors, Interleukin-17Recombinant ProteinsSurvival AnalysisT-Lymphocytes, CytotoxicTreatment OutcomeViral LoadVirus ReplicationWest Nile FeverWest Nile virusConceptsT cell cytotoxicityRecombinant IL-17AWest Nile virus infectionWNV-infected miceIL-17AT cellsViral burdenWNV infectionCell cytotoxicityInterleukin-17AVirus infectionMicrobial infectionsIL-17A-deficient miceT cell-mediated clearanceHigh viral burdenT-cell axisLethal WNV infectionSurvival of miceDay 6 postinfectionT cell functionWild-type miceDiverse immune functionsIL-17A.Proinflammatory cytokinesAutoimmune diseasesTLR8 Couples SOCS-1 and Restrains TLR7-Mediated Antiviral Immunity, Exacerbating West Nile Virus Infection in Mice
Paul AM, Acharya D, Le L, Wang P, Stokic DS, Leis AA, Alexopoulou L, Town T, Flavell RA, Fikrig E, Bai F. TLR8 Couples SOCS-1 and Restrains TLR7-Mediated Antiviral Immunity, Exacerbating West Nile Virus Infection in Mice. The Journal Of Immunology 2016, 197: 4425-4435. PMID: 27798161, PMCID: PMC5123688, DOI: 10.4049/jimmunol.1600902.Peer-Reviewed Original ResearchConceptsWest Nile virusAntiviral immunityWNV infectionWest Nile virus infectionOverexpression of TLR7Induced IFNsWild-type controlsSuppressor of cytokineTLR7 expressionNeuronal deathVirus infectionHuman TLR7TLR7TLR8InfectionMiceX proteinReduced expressionImmunityNile virusSOCS-1RNA knockdownIFNNovel roleProapoptotic genes
2014
Immune Markers Associated with Host Susceptibility to Infection with West Nile Virus
Qian F, Thakar J, Yuan X, Nolan M, Murray KO, Lee WT, Wong SJ, Meng H, Fikrig E, Kleinstein SH, Montgomery RR. Immune Markers Associated with Host Susceptibility to Infection with West Nile Virus. Viral Immunology 2014, 27: 39-47. PMID: 24605787, PMCID: PMC3949440, DOI: 10.1089/vim.2013.0074.Peer-Reviewed Original ResearchConceptsWest Nile virusSevere infectionsImmune markersIL-4IL-4 levelsSerum cytokine levelsSerum IL-4Nile virusSignificant risk factorsImmune system statusPeripheral blood cellsSevere neurological diseaseCytokine levelsAntibody levelsImmune statusRisk factorsHealthy subjectsStratified cohortWNV infectionNeurological diseasesInfectionAltered expression levelsBlood cellsAltered gene expression patternsHost susceptibility
2013
ELF4 is critical for induction of type I interferon and the host antiviral response
You F, Wang P, Yang L, Yang G, Zhao YO, Qian F, Walker W, Sutton R, Montgomery R, Lin R, Iwasaki A, Fikrig E. ELF4 is critical for induction of type I interferon and the host antiviral response. Nature Immunology 2013, 14: 1237-1246. PMID: 24185615, PMCID: PMC3939855, DOI: 10.1038/ni.2756.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineCells, CulturedDNA-Binding ProteinsHEK293 CellsHeLa CellsHost-Pathogen InteractionsHumansImmunoblottingInterferon Regulatory Factor-3Interferon Regulatory Factor-7Interferon-betaMembrane ProteinsMiceMice, Inbred C57BLMice, KnockoutMicroscopy, ConfocalProtein BindingReverse Transcriptase Polymerase Chain ReactionRNA InterferenceSignal TransductionSurvival AnalysisTranscription FactorsTranscriptional ActivationWest Nile FeverWest Nile virus
2012
West Nile Virus: Biology, Transmission, and Human Infection
Colpitts TM, Conway MJ, Montgomery RR, Fikrig E. West Nile Virus: Biology, Transmission, and Human Infection. Clinical Microbiology Reviews 2012, 25: 635-648. PMID: 23034323, PMCID: PMC3485754, DOI: 10.1128/cmr.00045-12.Peer-Reviewed Original ResearchIL-22 Signaling Contributes to West Nile Encephalitis Pathogenesis
Wang P, Bai F, Zenewicz LA, Dai J, Gate D, Cheng G, Yang L, Qian F, Yuan X, Montgomery RR, Flavell RA, Town T, Fikrig E. IL-22 Signaling Contributes to West Nile Encephalitis Pathogenesis. PLOS ONE 2012, 7: e44153. PMID: 22952908, PMCID: PMC3429482, DOI: 10.1371/journal.pone.0044153.Peer-Reviewed Original ResearchConceptsWild-type miceCentral nervous systemIL-22Viral loadNeutrophil migrationType miceWest Nile virus encephalitisSimilar viral loadsLethal WNV infectionIL-22 signalingHost immune responseWNV neuroinvasionVirus encephalitisCXCR2 ligandsLeukocyte infiltrateProinflammatory cytokinesChemokine receptorsImmune responseWNV infectionViral infectionNervous systemSignaling contributesExtracellular pathogensNon-redundant roleWT leukocytesAntibodies against the Envelope Glycoprotein Promote Infectivity of Immature Dengue Virus Serotype 2
da Silva Voorham JM, Rodenhuis-Zybert IA, Nuñez N, Colpitts TM, van der Ende-Metselaar H, Fikrig E, Diamond MS, Wilschut J, Smit JM. Antibodies against the Envelope Glycoprotein Promote Infectivity of Immature Dengue Virus Serotype 2. PLOS ONE 2012, 7: e29957. PMID: 22431958, PMCID: PMC3303773, DOI: 10.1371/journal.pone.0029957.Peer-Reviewed Original ResearchConceptsAntibody-dependent enhancementImmature DENVAnti-prM antibodiesStructural proteins prMSevere dengue diseaseDengue virus antibodiesDengue virus serotype 2Dose-dependent mannerImmature particlesStandard virus preparationsVirus preparationsVirus antibodiesPrecursor membrane proteinVirus serotype 2Lethal infectionMouse modelDengue diseaseImmune serumDENV particlesProtein prMInfection studiesAntibodiesEnhanced infectivityInfectionSerotype 2Horizontal and Vertical Transmission of West Nile Virus Genotype NY99 by Culex salinarius and Genotypes NY99 and WN02 by Culex tarsalis
Anderson JF, Main AJ, Cheng G, Ferrandino FJ, Fikrig E. Horizontal and Vertical Transmission of West Nile Virus Genotype NY99 by Culex salinarius and Genotypes NY99 and WN02 by Culex tarsalis. American Journal Of Tropical Medicine And Hygiene 2012, 86: 134-139. PMID: 22232464, PMCID: PMC3247122, DOI: 10.4269/ajtmh.2012.11-0473.Peer-Reviewed Original Research
2011
Innate immune control of West Nile virus infection
Arjona A, Wang P, Montgomery RR, Fikrig E. Innate immune control of West Nile virus infection. Cellular Microbiology 2011, 13: 1648-1658. PMID: 21790942, PMCID: PMC3196381, DOI: 10.1111/j.1462-5822.2011.01649.x.Peer-Reviewed Original ResearchConceptsWest Nile virusWNV infectionAntiviral innate immune mechanismsLong-term neurologic sequelaeWest Nile virus infectionRe-emerging zoonotic pathogenInnate immune controlInnate immune mechanismsLife-threatening meningoencephalitisInnate immune systemNeurologic sequelaeImmune controlInflammatory mediatorsImmune mechanismsMammalian hostsVirus infectionCurrent evidenceViral infectionAntiviral effectorsImmune systemFlaviviridae familyAntiviral mechanismInfectionNile virusJAK-STATprM-antibody renders immature West Nile virus infectious in vivo
Colpitts TM, Rodenhuis-Zybert I, Moesker B, Wang P, Fikrig E, Smit JM. prM-antibody renders immature West Nile virus infectious in vivo. Journal Of General Virology 2011, 92: 2281-2285. PMID: 21697345, PMCID: PMC3347797, DOI: 10.1099/vir.0.031427-0.Peer-Reviewed Original ResearchConceptsWest Nile virusInfectious West Nile virusNile virusDeath of micePrM antibodiesNeurotropic pathogensWNV particlesSevere human diseasesFamily FlaviviridaeVivo proofImmature flavivirus particlesInfectious potentialAntibodiesDiseaseViral surfaceVirus particlesPrM proteinFlavivirus particlesVirusHuman diseasesInfectionMiceFlavivirusesBrainSerumImpaired Interferon Signaling in Dendritic Cells From Older Donors Infected In Vitro With West Nile Virus
Qian F, Wang X, Zhang L, Lin A, Zhao H, Fikrig E, Montgomery RR. Impaired Interferon Signaling in Dendritic Cells From Older Donors Infected In Vitro With West Nile Virus. The Journal Of Infectious Diseases 2011, 203: 1415-1424. PMID: 21398396, PMCID: PMC3080893, DOI: 10.1093/infdis/jir048.Peer-Reviewed Original ResearchConceptsDendritic cellsWest Nile virusOlder donorsAntiviral responseToll-like receptor 3Initial antiviral responseLate-phase responseNile virusSignificant age-related differencesSignificant human morbidityType I IFNQuantified cytokinesRNA flavivirusAge-related differencesYoung donorsI IFNReceptor RIGViral infectionReceptor 3Human morbidityOlder populationCritical regulatory pathwaysInterferon SignalingNuclear translocationDefective regulation
2010
A Paradoxical Role for Neutrophils in the Pathogenesis of West Nile Virus
Bai F, Kong KF, Dai J, Qian F, Zhang L, Brown CR, Fikrig E, Montgometry R. A Paradoxical Role for Neutrophils in the Pathogenesis of West Nile Virus. The Journal Of Infectious Diseases 2010, 202: 1804-1812. PMID: 21050124, PMCID: PMC3053000, DOI: 10.1086/657416.Peer-Reviewed Original ResearchConceptsWest Nile virusPolymorphonuclear leukocytesWNV infectionNile virusHigh viremiaViral clearanceEarly deathEarly infectionControl groupProtective roleBiphasic responseInnate immunityViral pathogenesisInfectionMiceViremiaPathogenesisParadoxical roleEfficient replicationVirusCXCL1CXCL2ChemokinesCXCR2NeutrophilsCaspase-12 controls West Nile virus infection via the viral RNA receptor RIG-I
Wang P, Arjona A, Zhang Y, Sultana H, Dai J, Yang L, LeBlanc PM, Doiron K, Saleh M, Fikrig E. Caspase-12 controls West Nile virus infection via the viral RNA receptor RIG-I. Nature Immunology 2010, 11: 912-919. PMID: 20818395, PMCID: PMC3712356, DOI: 10.1038/ni.1933.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCaspase 12Cells, CulturedDEAD Box Protein 58DEAD-box RNA HelicasesDNA-Binding ProteinsFibroblastsImmunity, InnateInterferon Type IMiceMice, Inbred C57BLMice, KnockoutNeuronsReceptors, VirusSignal TransductionTranscription FactorsUbiquitinationUbiquitin-Protein LigasesWest Nile FeverWest Nile virusTLR9-Targeted Biodegradable Nanoparticles as Immunization Vectors Protect against West Nile Encephalitis
Demento SL, Bonafé N, Cui W, Kaech SM, Caplan MJ, Fikrig E, Ledizet M, Fahmy TM. TLR9-Targeted Biodegradable Nanoparticles as Immunization Vectors Protect against West Nile Encephalitis. The Journal Of Immunology 2010, 185: 2989-2997. PMID: 20660705, PMCID: PMC3753007, DOI: 10.4049/jimmunol.1000768.Peer-Reviewed Original ResearchConceptsBiodegradable nanoparticlesUnmodified nanoparticlesImmune responseNanoparticlesCell-mediated immune responsesRobust humoral responseTh1 immune responseEffector T cellsAg-specific lymphocytesTh2-biased responsesAdjuvant aluminum hydroxideWest Nile encephalitisVirus encephalitisWest Nile virusAgHumoral responseCpG oligodeoxynucleotideT cellsMouse modelLive virusInfectious agentsProtein AgVaccine developmentWN virusNile virus
2009
IL-10 Signaling Blockade Controls Murine West Nile Virus Infection
Bai F, Town T, Qian F, Wang P, Kamanaka M, Connolly TM, Gate D, Montgomery RR, Flavell RA, Fikrig E. IL-10 Signaling Blockade Controls Murine West Nile Virus Infection. PLOS Pathogens 2009, 5: e1000610. PMID: 19816558, PMCID: PMC2749443, DOI: 10.1371/journal.ppat.1000610.Peer-Reviewed Original ResearchConceptsIL-10 signalingIL-10WNV infectionWest Nile virusIL-10-deficient miceWest Nile virus infectionImportant cellular sourceSignificant human morbidityRNA flavivirusWNV pathogenesisInterleukin-10Antiviral cytokinesEtiologic rolePharmacologic blockadeDeficient miceT cellsVirus infectionPharmacologic meansTherapeutic strategiesViral infectionCellular sourceInfectionHuman morbidityNile virusMiceFusion Loop Peptide of the West Nile Virus Envelope Protein Is Essential for Pathogenesis and Is Recognized by a Therapeutic Cross-Reactive Human Monoclonal Antibody
Sultana H, Foellmer HG, Neelakanta G, Oliphant T, Engle M, Ledizet M, Krishnan MN, Bonafé N, Anthony KG, Marasco WA, Kaplan P, Montgomery RR, Diamond MS, Koski RA, Fikrig E. Fusion Loop Peptide of the West Nile Virus Envelope Protein Is Essential for Pathogenesis and Is Recognized by a Therapeutic Cross-Reactive Human Monoclonal Antibody. The Journal Of Immunology 2009, 183: 650-660. PMID: 19535627, PMCID: PMC3690769, DOI: 10.4049/jimmunol.0900093.Peer-Reviewed Original ResearchConceptsWest Nile virus envelope proteinWest Nile virusVirus envelope proteinDengue virusCross-reactive human monoclonal antibodiesBlood-brain barrier permeabilityEnvelope proteinWest Nile virus infectionNeutralization escape variantsNile virusWest Nile encephalitisNeutralization escape mutantsHuman monoclonal antibodyFatal neurological diseaseParental West Nile virusFusion loopEscape variantsInflammatory responseBarrier permeabilityLethal encephalitisMAb11Virus infectionHuman mAbsEscape mutantsNeurological diseasesInflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy
Demento SL, Eisenbarth SC, Foellmer HG, Platt C, Caplan MJ, Saltzman W, Mellman I, Ledizet M, Fikrig E, Flavell RA, Fahmy TM. Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy. Vaccine 2009, 27: 3013-3021. PMID: 19428913, PMCID: PMC2695996, DOI: 10.1016/j.vaccine.2009.03.034.Peer-Reviewed Original ResearchMeSH KeywordsAdjuvants, ImmunologicAnimalsAntibody FormationCarrier ProteinsCD8-Positive T-LymphocytesDendritic CellsLactic AcidLipopolysaccharidesMiceMice, Inbred C57BLNanoparticlesNLR Family, Pyrin Domain-Containing 3 ProteinPolyglycolic AcidPolylactic Acid-Polyglycolic Acid CopolymerVaccinationViral Envelope ProteinsWest Nile FeverWest Nile Virus VaccinesConceptsPattern recognition receptorsToll-like receptorsInflammasome activationInnate immune system activationEffective adaptive immune responseIntracellular pattern recognition receptorsAntigen-presenting cellsAdaptive immune responsesWest Nile encephalitisImmune system activationInnate immune pathwaysWild-type macrophagesDendritic cellsCellular immunityVaccination approachesVaccine efficacyIL-1betaNLRP3 inflammasomeAdjuvant systemImmune responsePotent new approachMurine modelInflammasome activitySystem activationImmune pathwaysToll-like Receptor 7 Mitigates Lethal West Nile Encephalitis via Interleukin 23-Dependent Immune Cell Infiltration and Homing
Town T, Bai F, Wang T, Kaplan AT, Qian F, Montgomery RR, Anderson JF, Flavell RA, Fikrig E. Toll-like Receptor 7 Mitigates Lethal West Nile Encephalitis via Interleukin 23-Dependent Immune Cell Infiltration and Homing. Immunity 2009, 30: 242-253. PMID: 19200759, PMCID: PMC2707901, DOI: 10.1016/j.immuni.2008.11.012.Peer-Reviewed Original ResearchConceptsToll-like receptor 7West Nile virusReceptor 7WNV infectionImmune cell infiltrationLethal WNV infectionMyeloid differentiation factorIL-23 p19IL-23 responsesIL-12 p40West Nile encephalitisIL-12 p35Infected target cellsHost defense mechanismsRNA flavivirusInnate cytokinesWNV encephalitisInterleukin-12Cell infiltrationImmune cellsTarget organsVariable severityMiceTarget cellsTissue concentrations