2024
Leishmania major surface components and DKK1 signalling via LRP6 promote migration and longevity of neutrophils in the infection site
Ihedioha O, Marcarian H, Sivakoses A, Beverley S, McMahon-Pratt D, Bothwell A. Leishmania major surface components and DKK1 signalling via LRP6 promote migration and longevity of neutrophils in the infection site. Frontiers In Immunology 2024, 15: 1473133. PMCID: PMC11534728, DOI: 10.3389/fimmu.2024.1473133.Peer-Reviewed Original ResearchParasite-infected miceBALB/c miceDickkopf-1Infection siteInfected BALB/c micePathogen-associated molecular patternsWild-type BALB/c miceLevels of apoptosisNull mutantsLeishmania infectionDickkopf-1 levelsDraining lymph nodesNeutrophil-platelet aggregatesLeukocyte-platelet aggregatesInfiltration of neutrophilsReduced neutrophil activationDay 3 PIResponse to infectionSignaling pathwayHost-related factorsMolecular patternsMembrane componentsLRP6Lymph nodesTh2 differentiation
2023
Leishmania major-derived lipophosphoglycan influences the host’s early immune response by inducing platelet activation and DKK1 production via TLR1/2
Ihedioha O, Sivakoses A, Beverley S, McMahon-Pratt D, Bothwell A. Leishmania major-derived lipophosphoglycan influences the host’s early immune response by inducing platelet activation and DKK1 production via TLR1/2. Frontiers In Immunology 2023, 14: 1257046. PMID: 37885890, PMCID: PMC10598878, DOI: 10.3389/fimmu.2023.1257046.Peer-Reviewed Original ResearchConceptsLeukocyte-platelet aggregatesEarly immune responseImmune responsePlatelet activationHost's early immune responseCell-mediated immune responsesTh2 cell polarizationAdaptive immune responsesPro-inflammatory responsePattern recognition receptorsKey virulence factorsRecognition receptorsInfectious diseasesPathogenic moleculesEndothelial cellsWnt antagonistsInfection siteVirulence factorsTLR1/2PlateletsDickkopf1Cell typesLipophosphoglycanActivationResponse
2019
- Vaccine-based therapiesPublic health interventionsMechanism of actionTreatment of cancerCurrent vaccinesDisease preventionVaccine developmentHealth interventionsInfectious diseasesVaccinationDrug addictionVaccinePreventionTreatmentDelivery systemHospitalizationAllergyAdjuvantTherapyIllnessCancerDiseaseCDC
2017
Local Delivery of the Toll-Like Receptor 9 Ligand CpG Downregulates Host Immune and Inflammatory Responses, Ameliorating Established Leishmania (Viannia) panamensis Chronic Infection
Ehrlich AK, Fernández OL, Rodriguez-Pinto D, Castilho TM, Caridad M, Goldsmith-Pestana K, Saravia NG, McMahon-Pratt D. Local Delivery of the Toll-Like Receptor 9 Ligand CpG Downregulates Host Immune and Inflammatory Responses, Ameliorating Established Leishmania (Viannia) panamensis Chronic Infection. Infection And Immunity 2017, 85: 10.1128/iai.00981-16. PMID: 28052994, PMCID: PMC5328479, DOI: 10.1128/iai.00981-16.Peer-Reviewed Original ResearchConceptsAntigen-presenting cellsPeripheral blood mononuclear cellsCutaneous leishmaniasisB cellsIL-17IL-13Inflammatory responseMouse modelToll-like receptor 9 ligand CpGAlternate therapeutic approachCurrent treatment optionsBlood mononuclear cellsMixed inflammatory responseRegulatory cell functionProduction of IFNPredominant etiologic agentDose-response effectHost immune responseCell populationsGrowth factor βCpG treatmentRegulatory cellsChemokine responsesIL-10Host Immune
2016
Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness
Abdeen S, Salim N, Mammadova N, Summers CM, Goldsmith-Pestana K, McMahon-Pratt D, Schultz PG, Horwich AL, Chapman E, Johnson SM. Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness. Bioorganic & Medicinal Chemistry Letters 2016, 26: 5247-5253. PMID: 27720295, DOI: 10.1016/j.bmcl.2016.09.051.Peer-Reviewed Original ResearchConceptsT. brucei infectionBrucei infectionComplex treatment regimensFirst-line drugsNew therapeutic strategiesLeishmania major promastigotesAnti-parasitic potentialTreatment regimensTherapeutic windowTherapeutic strategiesCurrent drugsMajor promastigotesEncouraging initial resultsHuman liverAntibiotic resistanceGreater cytotoxicityProtozoan parasiteKidney cellsMedicinal chemistry optimizationInfectionInhibitorsPotent inhibitorBrucei parasitesDrugsCytotoxicityImmunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model
Siefert AL, Ehrlich A, Corral MJ, Goldsmith-Pestana K, McMahon-Pratt D, Fahmy TM. Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model. Biomaterials 2016, 108: 168-176. PMID: 27636154, PMCID: PMC5049880, DOI: 10.1016/j.biomaterials.2016.09.004.Peer-Reviewed Original ResearchConceptsPathogen-associated molecular patternsAccumulation of MDSCsHyper-inflammatory responseOngoing immune responseCytokine IL-10Antigen-presenting cellsCurrent treatment strategiesInflammation-mediated diseasesLong treatment regimensSite of infectionNew World leishmaniasisCellular immunomodulationIL-17Suppressor cellsDendritic cellsIL-10Immunotherapeutic approachesChronic inflammationTreatment regimensIL-13Free CpGTreatment strategiesTherapeutic effectImmune responsePreclinical studiesLeishmania‐encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence
Holowka T, Castilho TM, Garcia AB, Sun T, McMahon‐Pratt D, Bucala R. Leishmania‐encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence. The FASEB Journal 2016, 30: 2249-2265. PMID: 26956417, PMCID: PMC4871794, DOI: 10.1096/fj.201500189r.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, Differentiation, B-LymphocyteApoptosisCD4-Positive T-LymphocytesCloning, MolecularGene DeletionGene Expression RegulationHistocompatibility Antigens Class IILeishmania majorLeishmaniasis, CutaneousMacrophage Migration-Inhibitory FactorsMacrophagesMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMice, SCIDOrganisms, Genetically ModifiedProtein Array AnalysisProtozoan ProteinsConceptsMacrophage migration inhibitory factorMigration inhibitory factorCD4 T cellsInhibitory factorL. majorT cellsHost immunityProtective CD4 T cellsEffector CD4 T cellsCytokine macrophage migration inhibitory factorMajor-infected miceT cell primingAntigen-presenting cellsT cell formationExpression of IFNDeath-1Functional exhaustionIL-7RHost responseParasite persistenceParasite burdenParasite growthReduced expressionMiceSignificant differencesThe Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation
Chae WJ, Ehrlich AK, Chan PY, Teixeira AM, Henegariu O, Hao L, Shin JH, Park JH, Tang WH, Kim ST, Maher SE, Goldsmith-Pestana K, Shan P, Hwa J, Lee PJ, Krause DS, Rothlin CV, McMahon-Pratt D, Bothwell AL. The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity 2016, 44: 246-258. PMID: 26872695, PMCID: PMC4758884, DOI: 10.1016/j.immuni.2016.01.008.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, DermatophagoidesAntigens, ProtozoanAsthmaBlood PlateletsCell DifferentiationCells, CulturedCytokinesExtracellular Signal-Regulated MAP KinasesGene Expression RegulationHumansInflammationIntercellular Signaling Peptides and ProteinsLeishmania majorLeishmaniasis, CutaneousMiceMice, Inbred BALB CMice, Inbred C57BLMice, TransgenicModels, AnimalPyroglyphidaeSignal TransductionTh2 CellsTOR Serine-Threonine KinasesWnt ProteinsConceptsCell-mediated inflammationTh2 cell cytokine productionCell cytokine productionLeukocyte-platelet aggregatesLeukocyte infiltrationDkk-1Cytokine productionT helper 2 cellsLeishmania major infectionHouse dust miteTranscription factor c-MafAllergen challengeMajor infectionDust miteImmune responseDickkopf-1Parasitic infectionsGATA-3Pathological roleFunctional inhibitionInflammationC-MafP38 MAPKInfiltrationInfectionThe Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection
Wetzel DM, Rhodes EL, Li S, McMahon-Pratt D, Koleske AJ. The Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection. Journal Of Cell Science 2016, 129: 3130-3143. PMID: 27358479, PMCID: PMC5004897, DOI: 10.1242/jcs.185595.Peer-Reviewed Original ResearchMeSH KeywordsAniline CompoundsAnimalsCytokinesDisease Models, AnimalImatinib MesylateImmunoglobulin GLeishmaniaLeishmaniasisMacrophagesMiceModels, BiologicalNitrilesParasitesPhagocytosisPhosphorylationProtein-Tyrosine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-hckPyrimidinesQuinolinesRAW 264.7 CellsSignal TransductionSrc-Family KinasesConceptsAmastigote uptakeObligate intracellular parasite LeishmaniaImmunoglobulin-mediated phagocytosisIntracellular parasite LeishmaniaNovel therapeutic strategiesPersistence of infectionLeishmania infectionIgG-mediated phagocytosisTherapeutic strategiesFc receptorsSmall molecule inhibitorsArg activationDisease severityParasite burdenPrimary macrophagesMacrophagesKinase inhibitorsLeishmaniasisHuman hostDevastating diseaseInfectionParasite LeishmaniaSrc family kinasesPhagocytosisLeishmania
2015
Cutaneous leishmaniasis is regulated by Wnt antagonist Dkk-1 from activated platelets (MPF7P.715)
Bothwell A, Chae W, Ehrlich A, Teixeira A, Goldsmith-Pestana K, Maher S, Hwa J, Krause D, McMahon-Pratt D. Cutaneous leishmaniasis is regulated by Wnt antagonist Dkk-1 from activated platelets (MPF7P.715). The Journal Of Immunology 2015, 194: 203.16-203.16. DOI: 10.4049/jimmunol.194.supp.203.16.Peer-Reviewed Original ResearchNeutrophil-platelet aggregate formationDkk-1Cutaneous leishmaniasisLate inflammatory responseSkin inflammatory diseasesT cell differentiationMajor infectionAntigen exposureLymph nodesChronic inflammationTh2 cytokinesInflammatory diseasesInflammatory responseTh2 cellsSkin lesionsSmall molecule inhibitorsParasite burdenGATA-3Functional inhibitionMarked inhibitionLeishmaniasisC-MafHuman plateletsMolecule inhibitorsPlatelets
2014
The Immunotherapeutic Role of Regulatory T Cells in Leishmania (Viannia) panamensis Infection
Ehrlich A, Castilho TM, Goldsmith-Pestana K, Chae WJ, Bothwell AL, Sparwasser T, McMahon-Pratt D. The Immunotherapeutic Role of Regulatory T Cells in Leishmania (Viannia) panamensis Infection. The Journal Of Immunology 2014, 193: 2961-2970. PMID: 25098291, PMCID: PMC4170189, DOI: 10.4049/jimmunol.1400728.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodiesAntigen-Antibody ComplexCell ProliferationFemaleImmunotherapy, AdoptiveIndoleamine-Pyrrole 2,3,-DioxygenaseInflammationInterferon-gammaInterleukin-10Interleukin-13Interleukin-17Interleukin-2Leishmania guyanensisLeishmaniasis, MucocutaneousLymphocyte CountMiceMice, Inbred BALB CMice, TransgenicParasite LoadT-Lymphocytes, RegulatoryTransforming Growth Factor betaConceptsRegulatory T cellsPanamensis infectionInflammatory responseT cellsLeishmania parasitesDisease pathologyImmunotherapeutic treatment approachesL. panamensis infectionsLeishmania panamensis infectionPercentage of TregsRIL-2/Th2 inflammatory responseIL-13 levelsParasite loadAlternate treatment strategiesT cell proliferationTreg functionalityDisease exacerbationAdoptive transferIL-17IL-10Naive miceCytokine responsesImmunotherapeutic roleCytokine productionChronicity of Dermal Leishmaniasis Caused by Leishmania panamensis Is Associated with Parasite-Mediated Induction of Chemokine Gene Expression
Navas A, Vargas DA, Freudzon M, McMahon-Pratt D, Saravia NG, Gómez MA. Chronicity of Dermal Leishmaniasis Caused by Leishmania panamensis Is Associated with Parasite-Mediated Induction of Chemokine Gene Expression. Infection And Immunity 2014, 82: 2872-2880. PMID: 24752514, PMCID: PMC4097649, DOI: 10.1128/iai.01133-13.Peer-Reviewed Original ResearchConceptsSelf-healed patientsChronic cutaneous leishmaniasisDermal leishmaniasisChemokine gene expressionClinical outcomesBiopsy specimensChronic diseasesInflammatory responseLeishmania panamensisExpression levelsCCR5 receptor geneInduction of CXCL5Montenegro skin testLesion biopsy specimensL. panamensisSelf-healing diseaseNew therapeutic targetsReverse transcription-quantitative PCRTranscription-quantitative PCRChemotactic chemokinesInflammation contributesSkin testAsymptomatic infectionInflammatory activationImmune cellsCD4 T cell activation by B cells in human Leishmania (Viannia)infection
Rodriguez-Pinto D, Saravia NG, McMahon-Pratt D. CD4 T cell activation by B cells in human Leishmania (Viannia)infection. BMC Infectious Diseases 2014, 14: 108. PMID: 24568275, PMCID: PMC3937821, DOI: 10.1186/1471-2334-14-108.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedB-LymphocytesBiotinCD4-Positive T-LymphocytesColombiaFemaleFlow CytometryFluorescein-5-isothiocyanateGene Expression RegulationHumansImmunoglobulin MInterferon-gammaInterleukin-6Leishmania braziliensisLeishmaniasis, CutaneousLeukocytes, MononuclearLymphocyte ActivationMaleMiddle AgedOvalbuminTumor Necrosis Factor-alphaYoung AdultConceptsCD4 T cellsCutaneous leishmaniasis patientsT cellsB cellsLeishmaniasis patientsT cell activationLeishmania antigenImmune responseCell activationT-cell activation parametersSpecific CD4 T cellsEffective adaptive immune responseCD4 T cell activationB-cell activation markersCultures of PBMCUpregulation of CD86Cell activation markersCostimulatory molecule CD86Activation markers CD25Adaptive immune responsesHuman cutaneous leishmaniasisPurified B cellsT cell culturesHuman B cell linesHuman B cells
2013
The role of regulatory T cells in the Leishmania (Viannia) panamensis mouse model: a target for immunotherapy. (P3091)
Ehrlich A, Castilho T, Goldsmith-Pestana K, Sparwasser T, McMahon-Pratt D. The role of regulatory T cells in the Leishmania (Viannia) panamensis mouse model: a target for immunotherapy. (P3091). The Journal Of Immunology 2013, 190: 187.17-187.17. DOI: 10.4049/jimmunol.190.supp.187.17.Peer-Reviewed Original ResearchIL-17IL-10Treg functionIL-13Mouse modelMixed Th1/Th2Ablation of TregsL. panamensis infectionsRegulatory T cellsTh1/Th2Treg suppressive functionAlternate treatment strategiesT cell proliferationAmelioration of diseaseDEREG micePanamensis infectionTreg impairmentTreg cellsAdoptive transferCpG treatmentDisease resolutionHyperinflammatory responseNaïve miceDisease progressionTreatment strategies
2012
Human Macrophage Response to L. (Viannia) panamensis: Microarray Evidence for an Early Inflammatory Response
Ramírez C, Díaz-Toro Y, Tellez J, Castilho TM, Rojas R, Ettinger NA, Tikhonova I, Alexander ND, Valderrama L, Hager J, Wilson ME, Lin A, Zhao H, Saravia NG, McMahon-Pratt D. Human Macrophage Response to L. (Viannia) panamensis: Microarray Evidence for an Early Inflammatory Response. PLOS Neglected Tropical Diseases 2012, 6: e1866. PMID: 23145196, PMCID: PMC3493378, DOI: 10.1371/journal.pntd.0001866.Peer-Reviewed Original ResearchConceptsMRNA abundance profilesMonocyte-derived macrophagesRegulation of genesDistinct biologic responsesAbundance profilesL. panamensisDifferential gene expressionEarly time pointsMacrophage responseEarly macrophage responseImmune responseLeishmania speciesHuman monocyte-derived macrophagesMicroarray evidenceOutset of infectionGene regulationActivation of PKCHuman macrophage responseGene expressionLeishmania panamensis infectionTime pointsCellular responsesAdaptive immune responsesG proteinsEarly inflammatory responseThe Abl and Arg Kinases Mediate Distinct Modes of Phagocytosis and Are Required for Maximal Leishmania Infection
Wetzel DM, McMahon-Pratt D, Koleske AJ. The Abl and Arg Kinases Mediate Distinct Modes of Phagocytosis and Are Required for Maximal Leishmania Infection. Molecular And Cellular Biology 2012, 32: 3176-3186. PMID: 22665498, PMCID: PMC3434515, DOI: 10.1128/mcb.00086-12.Peer-Reviewed Original ResearchConceptsComplement receptor 3Leishmania infectionIgG-coated beadsMurine cutaneous leishmaniasisPotential therapeutic targetLeishmania uptakeVisceral diseaseObligate intracellular parasitesCutaneous leishmaniasisTherapeutic targetFc receptorsAmastigote uptakeTreatment resultsReceptor 3Small lesionsInfection severityLeishmania amazonensisKinase inhibitorsIntracellular parasitesBead phagocytosisPhagocytosisReceptorsC3biInfectionLeishmaniasis
2011
TLR1/2 Activation during Heterologous Prime-Boost Vaccination (DNA-MVA) Enhances CD8+ T Cell Responses Providing Protection against Leishmania (Viannia)
Jayakumar A, Castilho TM, Park E, Goldsmith-Pestana K, Blackwell JM, McMahon-Pratt D. TLR1/2 Activation during Heterologous Prime-Boost Vaccination (DNA-MVA) Enhances CD8+ T Cell Responses Providing Protection against Leishmania (Viannia). PLOS Neglected Tropical Diseases 2011, 5: e1204. PMID: 21695103, PMCID: PMC3114751, DOI: 10.1371/journal.pntd.0001204.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesDisease Models, AnimalFemaleGenetic VectorsImmunization, SecondaryInterferon-gammaInterleukin-10Interleukin-13LeishmaniaLeishmaniasisLeishmaniasis VaccinesMiceMice, Inbred BALB CPeroxidasesProtozoan ProteinsRodent DiseasesToll-Like Receptor 1Toll-Like Receptor 2VaccinationVaccines, DNAVaccines, SyntheticVaccinia virusViral VaccinesConceptsPrime-boost vaccinationHeterologous prime-boost vaccinationCD8 T cellsT cell responsesT cellsTLR1/2 activationIL-10Vaccination modalityIL-13Immune responseAntigen-specific CD8 cellsCD8 T cell responsesCell responsesL. panamensis infectionsSpecific CD8 cellsTLR1/2 agonist Pam3CSK4IL-10 responsesVaccine-induced protectionCD4 T cellsMurine immune responseIL-13 responsesLeishmania speciesInfection/diseaseVaccinia virus AnkaraInnate immune response
2010
Murine model of chronic L. (Viannia) panamensis infection: Role of IL‐13 in disease
Castilho TM, Goldsmith‐Pestana K, Lozano C, Valderrama L, Saravia NG, McMahon‐Pratt D. Murine model of chronic L. (Viannia) panamensis infection: Role of IL‐13 in disease. European Journal Of Immunology 2010, 40: 2816-2829. PMID: 20827674, PMCID: PMC3289133, DOI: 10.1002/eji.201040384.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAnimalsChronic DiseaseDisease Models, AnimalEnzyme-Linked Immunosorbent AssayFemaleHumansInterferon-gammaInterleukin-13LeishmaniaLeishmaniasis, CutaneousMaleMiceMice, Inbred BALB CMice, KnockoutMiddle AgedReceptors, Interleukin-4Th1 CellsTh2 CellsTumor Necrosis Factor-alphaYoung AdultConceptsL. panamensis infectionsIL-13Panamensis infectionChronic diseasesImmunodeficient miceMurine modelMixed Th1/Th2 responseBALB/c mouse modelTh1/Th2 responsePrevalent etiologic agentHuman cutaneous leishmaniasisPresence of TNFPrevention of leishmaniasisIL-17Immunological mechanismsTh2 responsesIL-10Recurrent lesionsChronic infectionEvident lesionsMice resemblesT cellsImmune responsePersistent infectionLeishmania organismsMegasomes in Leishmania
McMahon-Pratt D, Ueda-Nakamura T, Traub-Csekö Y. Megasomes in Leishmania. Microbiology Monographs 2010, 17: 131-148. DOI: 10.1007/978-3-642-12863-9_6.Peer-Reviewed Original ResearchImportance of lysosomesProtein traffickingLeishmania virulenceResident enzymesMammalian hostsLysosome-like structuresLeishmania mexicana complexParasite existLysosomal hydrolasesTargeting mechanismCysteine proteinasesSerious public health problemPublic health problemMexicana complexPhlebotomine sandfliesLesion amastigotesGenus LeishmaniaAmastigote formsGood targetClassic pathwayPathwayPromastigote formsHealth problemsMegasomesInsectsMurine visceral leishmaniasis: IgM and polyclonal B‐cell activation lead to disease exacerbation
Deak E, Jayakumar A, Cho KW, Goldsmith‐Pestana K, Dondji B, Lambris JD, McMahon‐Pratt D. Murine visceral leishmaniasis: IgM and polyclonal B‐cell activation lead to disease exacerbation. European Journal Of Immunology 2010, 40: 1355-1368. PMID: 20213734, PMCID: PMC2944234, DOI: 10.1002/eji.200939455.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, ProtozoanAntigen PresentationB-LymphocytesComplement C5aDisease ProgressionFemaleHypergammaglobulinemiaImmunity, InnateImmunization, PassiveImmunoglobulin GImmunoglobulin MInterleukin-10Leishmania infantumLeishmaniasis, VisceralLymph NodesLymphocyte ActivationLymphocyte DepletionMaleMiceMice, Inbred BALB CMice, TransgenicParasitemiaConceptsBALB/c miceC miceDisease exacerbationImmune responseVisceral leishmaniasisB cell-derived IL-10WT BALB/c miceB cell antigen presentationPolyclonal B cell activationAnti-Leishmania responseOngoing immune responseL. infantum infectionHuman visceral leishmaniasisBALB/cB cell expansionIntradermal infection modelB cell activationEstablishment of infectionElevated parasitemiaParasite visceralizationCytokine levelsIL-10Infantum infectionPassive transferAntigen presentation