2020
A Critical Role for STING Signaling in Limiting Pathogenesis of Chikungunya Virus
Geng T, Lin T, Yang D, Harrison AG, Vella AT, Fikrig E, Wang P. A Critical Role for STING Signaling in Limiting Pathogenesis of Chikungunya Virus. The Journal Of Infectious Diseases 2020, 223: 2186-2196. PMID: 33161431, PMCID: PMC8205639, DOI: 10.1093/infdis/jiaa694.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArthritisChikungunya FeverChikungunya virusImmunity, InnateMembrane ProteinsMiceMice, KnockoutViremiaConceptsVirus infectionSTING signalingGt miceType I IFN responseChikungunya virus infectionImmune cell infiltrationWild-type miceActivator of neutrophilsInnate immune responseExpression of interferonI IFN responseExpression of chemoattractantsRNA virus infectionDNA virus infectionInterferon genes (STING) pathwayCHIKV arthritisViremic stageArthritis progressionViral burdenArthritis pathogenesisChemokine responsesCell infiltrationJoint damageImmune responseSTING deficiencyCXCL10 Signaling Contributes to the Pathogenesis of Arthritogenic Alphaviruses
Lin T, Geng T, Harrison AG, Yang D, Vella AT, Fikrig E, Wang P. CXCL10 Signaling Contributes to the Pathogenesis of Arthritogenic Alphaviruses. Viruses 2020, 12: 1252. PMID: 33147869, PMCID: PMC7692144, DOI: 10.3390/v12111252.Peer-Reviewed Original ResearchConceptsChikungunya virusAlphaviral arthritisArthritogenic alphavirusesLargest immune cell populationMacrophages/T cellsImmune cell populationsInflammatory immune responseLow viral loadWild-type miceO'nyong-nyong virusWild-type animalsRheumatic manifestationsImmune infiltratesViral loadT cellsImmune responseAlphaviral diseaseArthritic diseasesTherapeutic targetCXCL10PathogenesisViral RNACell populationsArthritisFootpadMacrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy in mice
Yang L, Geng T, Yang G, Ma J, Wang L, Ketkar H, Yang D, Lin T, Hwang J, Zhu S, Wang Y, Dai J, You F, Cheng G, Vella AT, Flavell RA, Fikrig E, Wang P. Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy in mice. Communications Biology 2020, 3: 556. PMID: 33033362, PMCID: PMC7545163, DOI: 10.1038/s42003-020-01285-6.Peer-Reviewed Original ResearchConceptsMacrophage scavenger receptor 1Scavenger receptor 1Chikungunya virusReceptor 1Antiviral roleType I IFN responseChikungunya virus infectionLow-density lipoproteinImportant antiviral roleI IFN responseMarkers of autophagyCHIKV infectionViral loadArthritogenic alphavirusesVirus infectionCHIKV replicationATG5-ATG12Antiviral actionKnockout miceMSR1 expressionIFN responseInfectionMiceNsp1 proteinAutophagic function
2019
ELF4 facilitates innate host defenses against Plasmodium by activating transcription of Pf4 and Ppbp
Wang D, Zhang Z, Cui S, Zhao Y, Craft S, Fikrig E, You F. ELF4 facilitates innate host defenses against Plasmodium by activating transcription of Pf4 and Ppbp. Journal Of Biological Chemistry 2019, 294: 7787-7796. PMID: 30898878, PMCID: PMC6514618, DOI: 10.1074/jbc.ra118.006321.Peer-Reviewed Original ResearchConceptsPlatelet factor 4Host defenseComponent of plateletsPro-platelet basic proteinKilling of parasitesFactor 4Innate immune moleculesInnate immune signalingInnate host defenseC chemokinesWT littermatesTranscription factor 4Control animalsImmune moleculesInnate immunityInfected erythrocytesImmune signalingInfectionExpression levelsMiceType IBasic proteinDefense peptidesPlateletsPlasmodiumHIPK2 is necessary for type I interferon–mediated antiviral immunity
Cao L, Yang G, Gao S, Jing C, Montgomery RR, Yin Y, Wang P, Fikrig E, You F. HIPK2 is necessary for type I interferon–mediated antiviral immunity. Science Signaling 2019, 12 PMID: 30890658, PMCID: PMC6893850, DOI: 10.1126/scisignal.aau4604.Peer-Reviewed Original ResearchConceptsHomeodomain-interacting protein kinase 2Type I interferonProtein kinase 2I interferonRNA virus infectionAntiviral immunityN-terminal fragmentVesicular stomatitis virus infectionNuclear localizationActive caspasesKinase activityB transcriptionHIPK2 deficiencyKinase 2Virus infectionStomatitis virus infectionAntiviral responseWild-type miceVSV infectionModeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor
Marín-Lopez A, Calvo-Pinilla E, Moreno S, Utrilla-Trigo S, Nogales A, Brun A, Fikrig E, Ortego J. Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor. Viruses 2019, 11: 35. PMID: 30625992, PMCID: PMC6356211, DOI: 10.3390/v11010035.Peer-Reviewed Original ResearchConceptsMouse modelAnimal modelsArbovirus infectionInterferon α/β receptorAlpha/beta receptorAppropriate animal modelsNatural hostInterferon alpha/beta receptorSafe therapyProtective efficacyArboviral infectionsImmune responseAdult miceBeta receptorsNew vaccinesDisease pathogenesisExtrapolation of findingsΒ receptorExperimental infectionBiosafety level 3MiceInfectionStatistical significanceVirusPathogenesis
2018
MiR-221 negatively regulates innate anti-viral response
Du H, Cui S, Li Y, Yang G, Wang P, Fikrig E, You F. MiR-221 negatively regulates innate anti-viral response. PLOS ONE 2018, 13: e0200385. PMID: 30089112, PMCID: PMC6082502, DOI: 10.1371/journal.pone.0200385.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntagomirsDNA-Binding ProteinsDown-RegulationHEK293 CellsHerpesvirus 1, HumanHumansImmunity, InnateInterferon-betaMacrophagesMiceMice, Inbred C57BLMice, KnockoutMicroRNAsPromoter Regions, GeneticProtein Serine-Threonine KinasesRhabdoviridae InfectionsTranscription FactorsVesiculovirusConceptsAntiviral responseMiR-221Innate anti-viral responseInitial antiviral responseImmune cell activationMiR-221 expressionAnti-viral responseInnate antiviral responseInnate immune systemAnti-viral defenseIFNβ productionVirus infectionMultiple candidate targetsImmune systemCell activationCandidate targetsInfectionRNA-seq analysisCritical roleDirect bindingResponseMicroRNA regulatorsCircadian Rhythms Influence the Severity of Sepsis in Mice via a TLR2-Dependent, Leukocyte-Intrinsic Mechanism
Heipertz EL, Harper J, Lopez CA, Fikrig E, Hughes ME, Walker WE. Circadian Rhythms Influence the Severity of Sepsis in Mice via a TLR2-Dependent, Leukocyte-Intrinsic Mechanism. The Journal Of Immunology 2018, 201: ji1701677. PMID: 29760192, PMCID: PMC9351006, DOI: 10.4049/jimmunol.1701677.Peer-Reviewed Original ResearchConceptsImmune cellsZT 19C57BL/6 miceWorse outcomesTLR2 agonist lipoteichoic acidCircadian rhythmTLR2 knockout miceFemale C57BL/6 miceMale C57BL/6 miceSeverity of sepsisBone marrow chimerasTLR2-dependent mechanismIL-6 productionTLR2-DependentSepsis severityCecal ligationSepsis phenotypesSepsisC57BL/6 cellsSimilar outcomesMiceMouse cecumLipoteichoic acidMurine macrophagesCLPUBXN3B positively regulates STING-mediated antiviral immune responses
Yang L, Wang L, Ketkar H, Ma J, Yang G, Cui S, Geng T, Mordue DG, Fujimoto T, Cheng G, You F, Lin R, Fikrig E, Wang P. UBXN3B positively regulates STING-mediated antiviral immune responses. Nature Communications 2018, 9: 2329. PMID: 29899553, PMCID: PMC5998066, DOI: 10.1038/s41467-018-04759-8.Peer-Reviewed Original ResearchConceptsUbiquitin regulatory X domain-containing proteinAntiviral immune responseImmune responseDeficient immune responseDomain-containing proteinsInterferon genes (STING) signalingVesicular stomatitis virus infectionDiverse biological processesStomatitis virus infectionPhosphorylation of TBK1Physiological evidenceHerpes simplex virus 1Cre-loxP approachSimplex virus 1Virus infectionAdult miceGene signalingHSV-1Biological processesPhysiological functionsVirus 1MicePrimary cellsConsequent recruitmentResponse
2017
Zika virus causes testicular atrophy
Uraki R, Hwang J, Jurado KA, Householder S, Yockey LJ, Hastings AK, Homer RJ, Iwasaki A, Fikrig E. Zika virus causes testicular atrophy. Science Advances 2017, 3: e1602899. PMID: 28261663, PMCID: PMC5321463, DOI: 10.1126/sciadv.1602899.Peer-Reviewed Original ResearchConceptsZika virusTesticular atrophyAcute viremic phaseZIKV-infected miceMosquito-borne flavivirusTestosterone-producing Leydig cellsProgressive testicular atrophyZIKV persistenceFetal infectionViremic phaseNeonatal abnormalitiesSerum testosteroneZIKV infectionNeurological dysfunctionSubcutaneous injectionZIKV replicationLeydig cellsVirus replicationVertical transmissionEpithelial cellsMiceViral RNAReproductive deficienciesAtrophyMale fertilityMultiple UBXN family members inhibit retrovirus and lentivirus production and canonical NFκΒ signaling by stabilizing IκBα
Hu Y, O’Boyle K, Auer J, Raju S, You F, Wang P, Fikrig E, Sutton RE. Multiple UBXN family members inhibit retrovirus and lentivirus production and canonical NFκΒ signaling by stabilizing IκBα. PLOS Pathogens 2017, 13: e1006187. PMID: 28152074, PMCID: PMC5308826, DOI: 10.1371/journal.ppat.1006187.Peer-Reviewed Original ResearchConceptsGene expressionHundreds of genesCycle assaysNFκB pathwayCo-immunoprecipitation studiesMouse embryo fibroblastsDownstream effector functionsJurkat T cellsPrimary human fibroblastsEmbryonic lethalityFamily membersUBA domainUBXN1HIV gene expressionSingle-cycle assaysProtein turnoverEmbryo fibroblastsCell adhesionGlobal regulationCanonical NFκB pathwayNFκB signalingHuman fibroblastsLike receptorsPathwayKnockdown
2016
TLR8 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
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 virusMyD88 Deficiency Markedly Worsens Tissue Inflammation and Bacterial Clearance in Mice Infected with Treponema pallidum, the Agent of Syphilis
Silver AC, Dunne DW, Zeiss CJ, Bockenstedt LK, Radolf JD, Salazar JC, Fikrig E. MyD88 Deficiency Markedly Worsens Tissue Inflammation and Bacterial Clearance in Mice Infected with Treponema pallidum, the Agent of Syphilis. PLOS ONE 2013, 8: e71388. PMID: 23940747, PMCID: PMC3734110, DOI: 10.1371/journal.pone.0071388.Peer-Reviewed Original ResearchConceptsMyD88-deficient miceTreponema pallidumMyD88-deficient animalsResistance of miceToll-like receptorsWild-type miceMyD88-deficient macrophagesMacrophage-mediated clearanceHigh pathogen burdenMyD88 deficiencySpirochete Treponema pallidumWT miceTissue infiltratesBacterial clearanceExtensive inflammationTissue inflammationPlasma cellsControl animalsWT macrophagesMost TLRsAnimal modelsMixed mononuclearPathogen burdenMiceT. pallidum
2012
Receptor interacting protein-2 contributes to host defense against Anaplasma phagocytophilum infection
Sukumaran B, Ogura Y, Pedra JH, Kobayashi KS, Flavell RA, Fikrig E. Receptor interacting protein-2 contributes to host defense against Anaplasma phagocytophilum infection. Pathogens And Disease 2012, 66: 211-219. PMID: 22747758, PMCID: PMC3530031, DOI: 10.1111/j.1574-695x.2012.01001.x.Peer-Reviewed Original ResearchConceptsRip2-deficient miceHuman granulocytic anaplasmosisNOD-like receptorsPhagocytophilum infectionTick-borne infectious diseaseNOD1/NOD2Obligate intracellular bacterium Anaplasma phagocytophilumInflammatory protein-2Host immune responseInnate immune pathwaysProtein 2Anaplasma phagocytophilum infectionHuman primary neutrophilsBacterium Anaplasma phagocytophilumHigh bacterial loadWild-type controlsImmune controlIL-12Immune clearanceImmune responseImmune pathwaysHost responseKC responsesHost defenseInfectious diseasesSemaphorin 7A Contributes to West Nile Virus Pathogenesis through TGF-β1/Smad6 Signaling
Sultana H, Neelakanta G, Foellmer HG, Montgomery RR, Anderson JF, Koski RA, Medzhitov RM, Fikrig E. Semaphorin 7A Contributes to West Nile Virus Pathogenesis through TGF-β1/Smad6 Signaling. The Journal Of Immunology 2012, 189: 3150-3158. PMID: 22896629, PMCID: PMC3496209, DOI: 10.4049/jimmunol.1201140.Peer-Reviewed Original ResearchConceptsRole of Sema7AWNV infectionSemaphorin 7ATGF-β1Lethal West Nile virus infectionViral pathogenesisBlood-brain barrier permeabilityWest Nile Virus PathogenesisWest Nile virus infectionMurine cortical neuronsPrimary human macrophagesViral burdenWNV pathogenesisCortical neuronsBarrier permeabilityFlaviviral infectionsVirus infectionVirus pathogenesisNervous systemImmune systemPathogenesisInfectionHuman macrophagesSema7AMice
2010
Infectivity of Borrelia burgdorferi sensu lato is unaltered in C3-deficient mice
van Burgel ND, Balmus NC, Fikrig E, van Dam AP. Infectivity of Borrelia burgdorferi sensu lato is unaltered in C3-deficient mice. Ticks And Tick-borne Diseases 2010, 2: 20-26. PMID: 21771533, DOI: 10.1016/j.ttbdis.2010.10.003.Peer-Reviewed Original ResearchConceptsWT miceAbsence of C3B. burgdorferiB. afzeliiQuantitative PCRDifferent Borrelia speciesC3 knockout miceC3-deficient miceComplement-deficient miceWild-type miceB. afzelii infectionBorrelia burgdorferi sensu latoHuman complementInflammation scoreBurgdorferi sensu latoB. bavariensisAfzelii infectionBorrelia speciesKnockout miceMiceHeart tissueWeeksB. gariniiBurgdorferiSignificant differencesCaspase-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 virus
2009
The Urokinase Receptor (uPAR) Facilitates Clearance of Borrelia burgdorferi
Hovius JW, Bijlsma MF, van der Windt GJ, Wiersinga WJ, Boukens BJ, Coumou J, Oei A, de Beer R, de Vos AF, van 't Veer C, van Dam AP, Wang P, Fikrig E, Levi MM, Roelofs JJ, van der Poll T. The Urokinase Receptor (uPAR) Facilitates Clearance of Borrelia burgdorferi. PLOS Pathogens 2009, 5: e1000447. PMID: 19461880, PMCID: PMC2678258, DOI: 10.1371/journal.ppat.1000447.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArthritis, InfectiousBorrelia burgdorferiCell MovementHeartHistocytochemistryHumansLeukocytesLyme DiseaseMiceMice, Inbred C57BLMice, KnockoutMyocarditisPhagocytosisReceptors, Urokinase Plasminogen ActivatorSkinStatistics, NonparametricUp-RegulationUrinary BladderUrokinase-Type Plasminogen ActivatorConceptsB. burgdorferi numbersWT controlsPhagocytotic capacityC3H/HeN backgroundIL-1beta mRNA expressionBorrelia burgdorferiB. burgdorferi infectionRole of uPARSevere carditisBurgdorferi infectionImmune responseLeukocyte functionSpirochete Borrelia burgdorferiFibrinolytic systemPAI-1Facilitate clearanceMRNA expressionHuman leukocytesLyme borreliosisMiceB. burgdorferiCausative agentProteinase receptorUPARAdequate eradicationToll-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