2017
Infection-derived lipids elicit an immune deficiency circuit in arthropods
Shaw DK, Wang X, Brown LJ, Chávez AS, Reif KE, Smith AA, Scott AJ, McClure EE, Boradia VM, Hammond HL, Sundberg EJ, Snyder GA, Liu L, DePonte K, Villar M, Ueti MW, de la Fuente J, Ernst RK, Pal U, Fikrig E, Pedra JH. Infection-derived lipids elicit an immune deficiency circuit in arthropods. Nature Communications 2017, 8: 14401. PMID: 28195158, PMCID: PMC5316886, DOI: 10.1038/ncomms14401.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnaplasma marginaleAnaplasma phagocytophilumAnimalsArthropodsBorrelia burgdorferiCarrier ProteinsDisease Models, AnimalDrosophila melanogasterDrosophila ProteinsEscherichia coliFas-Associated Death Domain ProteinGene SilencingHEK293 CellsHumansImmunologic Deficiency SyndromesIxodesLipidsLyme DiseasePhosphatidylglycerolsRecombinant ProteinsRNA, Small InterferingSignal TransductionTranscription FactorsUbiquitin-Conjugating EnzymesUbiquitin-Protein LigasesX-Linked Inhibitor of Apoptosis ProteinConceptsAdaptor molecule FasImmune deficiency (IMD) pathwayPeptidoglycan recognition proteinsE3 ubiquitin ligaseLyme disease spirochete Borrelia burgdorferiIMD pathwayGram-negative bacteriaRecognition proteinsUbiquitin ligaseDeath domainApoptosis proteinDistinct bacteriaBiochemical interactionsMolecule FasSpirochete Borrelia burgdorferiReceptor networkA. marginaleProteinAnaplasma phagocytophilumBacteriaPathwayBorrelia burgdorferiInsectsLipidsArthropodsPathogen-mediated manipulation of arthropod microbiota to promote infection
Abraham NM, Liu L, Jutras BL, Yadav AK, Narasimhan S, Gopalakrishnan V, Ansari JM, Jefferson KK, Cava F, Jacobs-Wagner C, Fikrig E. Pathogen-mediated manipulation of arthropod microbiota to promote infection. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: e781-e790. PMID: 28096373, PMCID: PMC5293115, DOI: 10.1073/pnas.1613422114.Peer-Reviewed Original ResearchConceptsTerminal D-alanine residueHuman pathogensPathogen-mediated manipulationNumerous human pathogensCapacity of bacteriaWay microbesArthropod microbiotaD-alanine residuesA. phagocytophilumAntibacterial proteinsPeritrophic matrixBacterial biofilm formationGut microbiotaMolecular mechanismsBacterial peptidoglycanPentapeptide chainBiofilm formationIAFGPIxodes scapularis ticksDiverse infectious agentsHuman granulocytic anaplasmosisMicrobiotaProteinAntifreeze glycoproteinsAnaplasma phagocytophilum
2014
Anaplasma phagocytophilum surface protein AipA mediates invasion of mammalian host cells
Seidman D, Ojogun N, Walker NJ, Mastronunzio J, Kahlon A, Hebert KS, Karandashova S, Miller DP, Tegels BK, Marconi RT, Fikrig E, Borjesson DL, Carlyon JA. Anaplasma phagocytophilum surface protein AipA mediates invasion of mammalian host cells. Cellular Microbiology 2014, 16: 1133-1145. PMID: 24612118, PMCID: PMC4115035, DOI: 10.1111/cmi.12286.Peer-Reviewed Original ResearchConceptsGranulocytic anaplasmosisObligate intracellular bacteriumVivo infectionInfectionPhagocytophilum infectionTransmission feedingObligate intracellular pathogensInfected ticksIntracellular pathogensNon-phagocytic cellsIntracellular bacteriumHL-60 cellsHost cell invasionCell invasionAnaplasma phagocytophilumPeptide-specific antiserumOwn uptakeHost cellsAttractive targetInternalization stepMammalian cellsInvasion proteinsSurface proteinsCell morphotypesCells
2013
SERUM ANTIBODIES TO BORRELIA BURGDORFERI, ANAPLASMA PHAGOCYTOPHILUM, AND BABESIA MICROTI IN RECAPTURED WHITE-FOOTED MICE
Magnarelli LA, Williams SC, Norris SJ, Fikrig E. SERUM ANTIBODIES TO BORRELIA BURGDORFERI, ANAPLASMA PHAGOCYTOPHILUM, AND BABESIA MICROTI IN RECAPTURED WHITE-FOOTED MICE. Journal Of Wildlife Diseases 2013, 49: 294-302. PMID: 23568904, PMCID: PMC3712766, DOI: 10.7589/2012-06-172.Peer-Reviewed Original ResearchConceptsB. microtiA. phagocytophilumB. burgdorferiBabesia microtiSolid-phase enzyme-linked immunosorbent assayAnaplasma phagocytophilumMouse immune systemEnzyme-linked immunosorbent assayIndirect fluorescent antibodyAntibody statusAntibody titersBorrelia burgdorferi sensu strictoSerum antibodiesTotal antibodyAntibody prevalenceNegative statusBurgdorferi sensu strictoImmune systemPatent infectionsEnd pointMiceImmunosorbent assayAntibodiesBorrelia burgdorferiFluorescent antibody
2012
Anaplasma phagocytophilum Outer Membrane Protein A Interacts with Sialylated Glycoproteins To Promote Infection of Mammalian Host Cells
Ojogun N, Kahlon A, Ragland SA, Troese MJ, Mastronunzio JE, Walker NJ, VieBrock L, Thomas RJ, Borjesson DL, Fikrig E, Carlyon JA. Anaplasma phagocytophilum Outer Membrane Protein A Interacts with Sialylated Glycoproteins To Promote Infection of Mammalian Host Cells. Infection And Immunity 2012, 80: 3748-3760. PMID: 22907813, PMCID: PMC3486060, DOI: 10.1128/iai.00654-12.Peer-Reviewed Original ResearchConceptsMammalian host cellsHuman granulocytic anaplasmosisHost cellsHL-60 cellsA. phagocytophilum organismsExtracellular domainP-selectin glycoprotein-1Outer Membrane Protein ASialylated glycoproteinsA. phagocytophilum infectionA. phagocytophilum-infected ticksN-terminal regionMembrane protein AObligate intracellular bacteriumAmino acids 19HGA patientsPhagocytophilum infectionInfectionTransmission feedingGlutathione S-transferaseGranulocytic anaplasmosisIntracellular bacteriumGlycoprotein 1Anaplasma phagocytophilumA. phagocytophilumIxodes scapularis JAK-STAT Pathway Regulates Tick Antimicrobial Peptides, Thereby Controlling the Agent of Human Granulocytic Anaplasmosis
Liu L, Dai J, Zhao YO, Narasimhan S, Yang Y, Zhang L, Fikrig E. Ixodes scapularis JAK-STAT Pathway Regulates Tick Antimicrobial Peptides, Thereby Controlling the Agent of Human Granulocytic Anaplasmosis. The Journal Of Infectious Diseases 2012, 206: 1233-1241. PMID: 22859824, PMCID: PMC3448968, DOI: 10.1093/infdis/jis484.Peer-Reviewed Original ResearchConceptsJAK-STAT pathwayTick salivary glandsA. phagocytophilum infectionAntimicrobial peptidesElectrophoretic mobility shift assaysPeptide-encoding genesMobility shift assaysPhagocytophilum infectionHuman granulocytic anaplasmosisGene familyTransducer activatorMammalian hostsRNA interferenceShift assaysTranscription pathwayGene expressionJAK-STATJanus kinaseGranulocytic anaplasmosisSalivary glandsPathwayGenesCritical roleAnaplasma phagocytophilumKey rolePostgenomic Analyses Reveal Development of Infectious Anaplasma phagocytophilum during Transmission from Ticks to Mice
Mastronunzio JE, Kurscheid S, Fikrig E. Postgenomic Analyses Reveal Development of Infectious Anaplasma phagocytophilum during Transmission from Ticks to Mice. Journal Of Bacteriology 2012, 194: 2238-2247. PMID: 22389475, PMCID: PMC3347074, DOI: 10.1128/jb.06791-11.Peer-Reviewed Original ResearchConceptsOpen reading frameA. phagocytophilum genomeObligate intracellular bacteriaBlood-feeding arthropodsCell surface proteinsMammalian cell cultureRickettsiales orderUncharacterized proteinsRibosomal proteinsEssential proteinsTranscriptome sequencingBacterial adaptationA. phagocytophilumDNA replicationTick salivary glandsPostgenomic analysisReading frameMammalian hostsAnaplasma phagocytophilumDevelopmental transitionsDC-specific markerIntracellular bacteriaTransmission feedingSurface proteinsProtein
2011
Ixodes scapularis salivary gland protein P11 facilitates migration of Anaplasma phagocytophilum from the tick gut to salivary glands
Liu L, Narasimhan S, Dai J, Zhang L, Cheng G, Fikrig E. Ixodes scapularis salivary gland protein P11 facilitates migration of Anaplasma phagocytophilum from the tick gut to salivary glands. EMBO Reports 2011, 12: 1196-1203. PMID: 21921936, PMCID: PMC3207102, DOI: 10.1038/embor.2011.177.Peer-Reviewed Original ResearchConceptsA. phagocytophilum infectionSalivary glandsA. phagocytophilumPhagocytophilum infectionAnaplasma phagocytophilumTick gutA. phagocytophilum-infected mice
2010
Anaplasma phagocytophilum AptA modulates Erk1/2 signalling
Sukumaran B, Mastronunzio JE, Narasimhan S, Fankhauser S, Uchil PD, Levy R, Graham M, Colpitts TM, Lesser CF, Fikrig E. Anaplasma phagocytophilum AptA modulates Erk1/2 signalling. Cellular Microbiology 2010, 13: 47-61. PMID: 20716207, PMCID: PMC3005019, DOI: 10.1111/j.1462-5822.2010.01516.x.Peer-Reviewed Original ResearchConceptsA. phagocytophilum infectionPhagocytophilum infectionCommon tick-borne diseasesHuman granulocytic anaplasmosisActivation of ERK1/2ERK1/2 mitogen-activated protein kinasesA. phagocytophilum survivalPolymorphonuclear leucocytesMitogen-activated protein kinaseHuman neutrophilsObligate intracellular pathogensGranulocytic anaplasmosisIntracellular pathogensTick-borne diseasesInfectionERK1/2 activationAnaplasma phagocytophilumVimentinSurvivalActivationBacterial inclusionsHost proteinsIntermediate filament protein vimentinVirulence proteinsProtein vimentinFucosylation enhances colonization of ticks by Anaplasma phagocytophilum
Pedra JH, Narasimhan S, Rendić D, DePonte K, Bell‐Sakyi L, Wilson IB, Fikrig E. Fucosylation enhances colonization of ticks by Anaplasma phagocytophilum. Cellular Microbiology 2010, 12: 1222-1234. PMID: 20331643, PMCID: PMC3250644, DOI: 10.1111/j.1462-5822.2010.01464.x.Peer-Reviewed Original ResearchConceptsA. phagocytophilumAnaplasma phagocytophilumHuman granulocytic anaplasmosisBacterium Anaplasma phagocytophilumGranulocytic anaplasmosisPathological processesTick feedingPhagocytophilumMicrobial pathogenesisNovel mechanismPathogen colonizationTick cellsFucosylated structuresTicksPathogen invasionPathogenesisAnaplasma phagocytophilum induces actin phosphorylation to selectively regulate gene transcription in Ixodes scapularis ticks
Sultana H, Neelakanta G, Kantor FS, Malawista SE, Fish D, Montgomery RR, Fikrig E. Anaplasma phagocytophilum induces actin phosphorylation to selectively regulate gene transcription in Ixodes scapularis ticks. Journal Of Experimental Medicine 2010, 207: 1727-1743. PMID: 20660616, PMCID: PMC2916137, DOI: 10.1084/jem.20100276.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnaplasma phagocytophilumAnimalsCell LineCell NucleusEnzyme InhibitorsGastrointestinal TractGene ExpressionGene Expression RegulationGTP-Binding Protein beta SubunitsGTP-Binding Protein gamma SubunitsInsect ProteinsIxodesP21-Activated KinasesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphorylationPromoter Regions, GeneticProtein BindingRNA InterferenceRNA Polymerase IISalivary GlandsSalivary Proteins and PeptidesSignal TransductionTATA-Box Binding ProteinTranscription, GeneticConceptsRNA polymerase IIActin phosphorylationTATA box-binding proteinNuclear G-actinPhosphorylation of actinP21-activated kinaseA. phagocytophilumA. phagocytophilum survivalTick cell linesIxodes scapularis ticksPolymerase IIPhosphorylated actinGene crucialGbetagamma subunitsGene transcriptionFilamentous actinAnaplasma phagocytophilumGene expressionBacterial acquisitionScapularis ticksPhosphorylationG-actinIntracellular pathogensMedical importanceActinSEASONAL PREVALENCE OF SERUM ANTIBODIES TO WHOLE CELL AND RECOMBINANT ANTIGENS OF BORRELIA BURGDORFERI AND ANAPLASMA PHAGOCYTOPHILUM IN WHITE-TAILED DEER IN CONNECTICUT
Magnarelli LA, Williams SC, Fikrig E. SEASONAL PREVALENCE OF SERUM ANTIBODIES TO WHOLE CELL AND RECOMBINANT ANTIGENS OF BORRELIA BURGDORFERI AND ANAPLASMA PHAGOCYTOPHILUM IN WHITE-TAILED DEER IN CONNECTICUT. Journal Of Wildlife Diseases 2010, 46: 781-790. PMID: 20688684, DOI: 10.7589/0090-3558-46.3.781.Peer-Reviewed Original ResearchConceptsRecombinant antigensInfected Ixodes scapularis ticksCoexistence of antibodiesAnaplasma phagocytophilumRespective causative agentsTick-borne infectionsEnzyme-linked immunosorbent assayIndirect fluorescent antibodyHuman granulocytic anaplasmosisPolyvalent enzyme-linked immunosorbent assaysIxodes scapularis ticksWhole blood samplesAntibody titersCurrent infectionWhole-cell B. burgdorferiBorrelia burgdorferi sensu strictoSerum antibodiesTotal antibodyBlood samplesHigher antibodyBurgdorferi sensu strictoSpecific recombinant antigensLyme borreliosisDeer seraImmunosorbent assay
2008
Anaplasma phagocytophilum Increases Cathepsin L Activity, Thereby Globally Influencing Neutrophil Function
Thomas V, Samanta S, Fikrig E. Anaplasma phagocytophilum Increases Cathepsin L Activity, Thereby Globally Influencing Neutrophil Function. Infection And Immunity 2008, 76: 4905-4912. PMID: 18765732, PMCID: PMC2573316, DOI: 10.1128/iai.00851-08.Peer-Reviewed Original ResearchMeSH KeywordsAnaplasma phagocytophilumCathepsin LCathepsinsCysteine EndopeptidasesEhrlichiosisElectrophoretic Mobility Shift AssayGene Expression Regulation, BacterialHL-60 CellsHomeodomain ProteinsHumansImmunoblottingImmunoprecipitationNeutrophilsNuclear ProteinsRepressor ProteinsReverse Transcriptase Polymerase Chain ReactionTranscription FactorsConceptsA. phagocytophilum infectionPhagocytophilum infectionCathepsin L activityNeutrophil functionA. phagocytophilumL activityHuman neutrophil peptides 1Polymorphonuclear leukocyte functionNeutrophil peptide-1Human granulocytic anaplasmosisTherapeutic optionsNeutrophil defenseLeukocyte functionCathepsin LPeptide-1InfectionObligate intracellular pathogensMarked reductionGranulocytic anaplasmosisIntracellular pathogensCDP activityHost oxidative burstAnaplasma phagocytophilumPhagocytophilumOxidative burst
2007
c-Jun NH2-Terminal Kinase 2 Inhibits Gamma Interferon Production during Anaplasma phagocytophilum Infection
Pedra JH, Mattner J, Tao J, Kerfoot SM, Davis RJ, Flavell RA, Askenase PW, Yin Z, Fikrig E. c-Jun NH2-Terminal Kinase 2 Inhibits Gamma Interferon Production during Anaplasma phagocytophilum Infection. Infection And Immunity 2007, 76: 308-316. PMID: 17998313, PMCID: PMC2223674, DOI: 10.1128/iai.00599-07.Peer-Reviewed Original ResearchConceptsIFN-gamma productionA. phagocytophilum infectionPhagocytophilum infectionIFN-gammaJnk2-null miceNatural killer T cellsA. phagocytophilumKiller T cellsIFN-gamma releaseIFN-gamma secretionGamma interferon productionT cell agonistsAnaplasma phagocytophilum infectionT cellsEarly eradicationGamma interferonInterferon productionInfectionC-Jun NH2-terminal kinase-2Inhibitory effectElevated levelsMiceAnaplasma phagocytophilumPhagocytophilumKinase 2ASC/PYCARD and Caspase-1 Regulate the IL-18/IFN-γ Axis during Anaplasma phagocytophilum Infection
Pedra JH, Sutterwala FS, Sukumaran B, Ogura Y, Qian F, Montgomery RR, Flavell RA, Fikrig E. ASC/PYCARD and Caspase-1 Regulate the IL-18/IFN-γ Axis during Anaplasma phagocytophilum Infection. The Journal Of Immunology 2007, 179: 4783-4791. PMID: 17878377, DOI: 10.4049/jimmunol.179.7.4783.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAnaplasmaAnaplasmosisAnimalsApoptosis Regulatory ProteinsCalcium-Binding ProteinsCaspase 1Disease SusceptibilityEnzyme ActivationHL-60 CellsHumansInterferon-gammaInterleukin-18Killer Cells, NaturalMiceMice, Inbred C57BLMice, KnockoutPhagocytosisSignal TransductionTh1 CellsT-Lymphocytes, RegulatoryConceptsA. phagocytophilum infectionIFN-gamma productionCaspase-1Phagocytophilum infectionIFN-gammaA. phagocytophilumIFN-gamma levelsNOD-like receptor pathwayIL-18 secretionIFN-gamma-mediated controlCentral adaptor moleculeAnaplasma phagocytophilum infectionVitro restimulationIL-18Peripheral bloodControl animalsReceptor pathwayASC deficiencyInfectionObligate intracellular pathogensIntracellular pathogensAnaplasma phagocytophilumPhagocytophilumAdaptor moleculeCritical roleIL-12/23p40-dependent clearance of Anaplasma phagocytophilum in the murine model of human anaplasmosis
Pedra JH, Tao J, Sutterwala FS, Sukumaran B, Berliner N, Bockenstedt LK, Flavell RA, Yin Z, Fikrig E. IL-12/23p40-dependent clearance of Anaplasma phagocytophilum in the murine model of human anaplasmosis. Pathogens And Disease 2007, 50: 401-410. PMID: 17521390, DOI: 10.1111/j.1574-695x.2007.00270.x.Peer-Reviewed Original ResearchConceptsIL-12/23p40Deficient miceT cellsImmune responseHuman anaplasmosisTh1 immune responseIFN-gamma productionDay 6 postinfectionAnaplasma phagocytophilumA. phagocytophilum burdenIL-23Dendritic cellsIL-12Neutrophil numbersIFN-gammaMurine modelMicrobial agonistsPathogen clearanceDependent clearanceInfectious diseasesEarly susceptibilityPathogen eliminationCausative agentA. phagocytophilumIndependent mechanismsAnaplasma phagocytophilum specifically induces tyrosine phosphorylation of ROCK1 during infection
Thomas V, Fikrig E. Anaplasma phagocytophilum specifically induces tyrosine phosphorylation of ROCK1 during infection. Cellular Microbiology 2007, 9: 1730-1737. PMID: 17346310, DOI: 10.1111/j.1462-5822.2007.00908.x.Peer-Reviewed Original ResearchConceptsAnaplasma phagocytophilumPSGL-1Non-antibiotic strategiesHuman granulocytic anaplasmosisA. phagocytophilum infectionA. phagocytophilum-infected cellsTick-borne agentsPolymorphonuclear leucocytesPromyelocytic cell linePhagocytophilum infectionObligate intracellular pathogensInfectionTyrosine phosphorylationIntracellular pathogensGranulocytic anaplasmosisCell linesROCK1SykPhagocytophilumPhosphorylationNeutrophilsLeucocytesAntibodies
2006
ANTIBODIES TO WHOLE-CELL OR RECOMBINANT ANTIGENS OF BORRELIA BURGDORFERI, ANAPLASMA PHAGOCYTOPHILUM, AND BABESIA MICROTI IN WHITE-FOOTED MICE
Magnarelli LA, Stafford KC, IJdo JW, Fikrig E. ANTIBODIES TO WHOLE-CELL OR RECOMBINANT ANTIGENS OF BORRELIA BURGDORFERI, ANAPLASMA PHAGOCYTOPHILUM, AND BABESIA MICROTI IN WHITE-FOOTED MICE. Journal Of Wildlife Diseases 2006, 42: 732-738. PMID: 17255439, DOI: 10.7589/0090-3558-42.4.732.Peer-Reviewed Original ResearchMeSH KeywordsAnaplasma phagocytophilumAnimalsAnimals, WildAntibodies, BacterialAntibodies, ProtozoanAntigens, BacterialAntigens, ProtozoanBabesia microtiBabesiosisBorrelia burgdorferiConnecticutEhrlichiosisEnzyme-Linked Immunosorbent AssayLyme DiseasePeromyscusRodent DiseasesSeroepidemiologic StudiesTick-Borne DiseasesConceptsEnzyme-linked immunosorbent assayB. burgdorferiOverall antibody prevalence rateBabesia microtiBorrelia burgdorferiAntibody prevalence ratesAnaplasma phagocytophilumA. phagocytophilumIndirect fluorescent antibodyWhite-footed miceWhole cell antigenTick-infested areasWhole-cell B. burgdorferiCurrent infectionPrevalence ratesMouse serumAntigenImmunosorbent assaySerum samplesRecombinant antigensAntibodiesSerumB. microtiMiceFluorescent antibodyAn Ixodes scapularis protein required for survival of Anaplasma phagocytophilum in tick salivary glands
Sukumaran B, Narasimhan S, Anderson JF, DePonte K, Marcantonio N, Krishnan MN, Fish D, Telford SR, Kantor FS, Fikrig E. An Ixodes scapularis protein required for survival of Anaplasma phagocytophilum in tick salivary glands. Journal Of Experimental Medicine 2006, 203: 1507-1517. PMID: 16717118, PMCID: PMC2118316, DOI: 10.1084/jem.20060208.Peer-Reviewed Original ResearchConceptsA. phagocytophilum-infected miceRNA interference-mediated silencingA. phagocytophilumTick salivary proteinsI. scapularis salivary glandsRickettsia-like pathogensTick salivary glandsMammalian hostsGenus RickettsiaAnaplasma phagocytophilumGene expressionSalivary glandsIntracellular organismsArthropodsSalivary proteinsPathogensProteinPhagocytophilumExpressionTicksHuman anaplasmosisSilencingGenesOrganismsAnaplasmaMechanisms of evasion of neutrophil killing by Anaplasma phagocytophilum
Carlyon JA, Fikrig E. Mechanisms of evasion of neutrophil killing by Anaplasma phagocytophilum. Current Opinion In Hematology 2006, 13: 28-33. PMID: 16319684, DOI: 10.1097/01.moh.0000190109.00532.56.Peer-Reviewed Original ResearchConceptsApoptosis differentiation programMitochondrial membrane integrityA. phagocytophilumCaspase-3 activationBacterium altersMolecular machineryVacuolar membraneTranscription factorsDifferentiation programMammalian hostsSecretory vesiclesAnaplasma phagocytophilumCytoplasmic compartmentGene expressionPromoter activityAntiapoptotic genesNADPH oxidase assemblyOxidase assemblyNeutrophil gene expressionHost cellsBacterial uptakeNADPH oxidase componentsMechanisms of evasionMembrane integrityCytochrome b558