Featured Publications
Effectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis
Vydyam P, Chand M, Pou S, Winter R, Liebman K, Nilsen A, Doggett J, Riscoe M, Mamoun C. Effectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis. ACS Infectious Diseases 2024, 10: 1405-1413. PMID: 38563132, PMCID: PMC11127568, DOI: 10.1021/acsinfecdis.4c00143.Peer-Reviewed Original ResearchConceptsRadical cureEndochin-like quinolonesAgent of human malariaLethal infection modelTreatment of human babesiosisLow toxicity profileExperimental mouse modelImmunocompetent miceImmunocompromised miceFavorable pharmacological propertiesHuman malariaToxicity profileChronic modelHuman babesiosisAnimal modelsInfection modelPharmacological limitationsActivity in vitroPharmacological propertiesReduce infectionQuinolonesMiceMitochondrial electron transport chainFavorable physicochemical propertiesMonotherapyTafenoquine-Atovaquone Combination Achieves Radical Cure and Confers Sterile Immunity in Experimental Models of Human Babesiosis
Vydyam P, Pal A, Renard I, Chand M, Kumari V, Gennaro J, Mamoun C. Tafenoquine-Atovaquone Combination Achieves Radical Cure and Confers Sterile Immunity in Experimental Models of Human Babesiosis. The Journal Of Infectious Diseases 2024, 229: 161-172. PMID: 38169301, PMCID: PMC10786256, DOI: 10.1093/infdis/jiad315.Peer-Reviewed Original ResearchBabesia BdFE1 esterase is required for the anti-parasitic activity of the ACE inhibitor fosinopril
Vydyam P, Choi J, Gihaz S, Chand M, Gewirtz M, Thekkiniath J, Lonardi S, Gennaro J, Mamoun C. Babesia BdFE1 esterase is required for the anti-parasitic activity of the ACE inhibitor fosinopril. Journal Of Biological Chemistry 2023, 299: 105313. PMID: 37797695, PMCID: PMC10663679, DOI: 10.1016/j.jbc.2023.105313.Peer-Reviewed Original ResearchConceptsAngiotensin converting enzyme (ACE) inhibitorsACE inhibitor fosinoprilTick-borne illnessConverting Enzyme InhibitorsVector-borne parasitic diseaseClass of drugsNovel drug targetsApicomplexan parasitesMass spectrometry analysisAnti-parasitic activityHeart failureSafe therapyParasite developmentDrug targetsEnzyme inhibitorsParasitic diseasesDrug resistanceTreatment of diseasesHuman babesiosisBabesia parasitesIntraerythrocytic parasitesSuch diseasesDiseaseSpectrometry analysisParasitesThe human malaria parasite Plasmodium falciparum can sense environmental changes and respond by antigenic switching
Schneider V, Visone J, Harris C, Florini F, Hadjimichael E, Zhang X, Gross M, Rhee K, Mamoun C, Kafsack B, Deitsch K. The human malaria parasite Plasmodium falciparum can sense environmental changes and respond by antigenic switching. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2302152120. PMID: 37068249, PMCID: PMC10151525, DOI: 10.1073/pnas.2302152120.Peer-Reviewed Original ResearchConceptsGene switchingGene expressionHistone methyltransferasesHuman malaria parasite Plasmodium falciparumMalaria parasite Plasmodium falciparumS-adenosylmethionineGene expression patternsMulticopy gene familiesVariant surface proteinsParasite Plasmodium falciparumHuman malaria parasiteIntracellular S-adenosylmethioninePrincipal methyl donorEpigenetic controlGene familyActive genesAntigenic switchingGene transcriptionNutrient availabilityExpression patternsMethylation modificationSAM metabolismGenetic modificationAntigenic variationSurface proteinsBabesia duncani multi-omics identifies virulence factors and drug targets
Singh P, Lonardi S, Liang Q, Vydyam P, Khabirova E, Fang T, Gihaz S, Thekkiniath J, Munshi M, Abel S, Ciampossin L, Batugedara G, Gupta M, Lu X, Lenz T, Chakravarty S, Cornillot E, Hu Y, Ma W, Gonzalez L, Sánchez S, Estrada K, Sánchez-Flores A, Montero E, Harb O, Le Roch K, Mamoun C. Babesia duncani multi-omics identifies virulence factors and drug targets. Nature Microbiology 2023, 8: 845-859. PMID: 37055610, PMCID: PMC10159843, DOI: 10.1038/s41564-023-01360-8.Peer-Reviewed Original ResearchConceptsDrug targetsVirulence factorsCandidate virulence factorsRNA-seq dataIntraerythrocytic life cycleAttractive drug targetB. duncaniNuclear genomeGenome annotationApicomplexan parasitesApicomplexan pathogensEpigenetic profilesEpigenetic analysisParasite metabolismMalaria-like diseaseHuman erythrocytesLife cycle stagesBabesia speciesGenomeMetabolic requirementsCycle stagesLife cycleBiologySmall moleculesPotent inhibitor
2024
A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria
Chahine Z, Abel S, Hollin T, Barnes G, Chung J, Daub M, Renard I, Choi J, Vydyam P, Pal A, Alba-Argomaniz M, Banks C, Kirkwood J, Saraf A, Camino I, Castaneda P, Cuevas M, De Mercado-Arnanz J, Fernandez-Alvaro E, Garcia-Perez A, Ibarz N, Viera-Morilla S, Prudhomme J, Joyner C, Bei A, Florens L, Ben Mamoun C, Vanderwal C, Le Roch K. A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria. Science 2024, 385: eadm7966. PMID: 39325875, DOI: 10.1126/science.adm7966.Peer-Reviewed Original ResearchConceptsP. falciparum malariaHumanized mouse modelPlasmodium falciparum</i> strainsIn vivo studiesParasite apicoplastDrug sensitivityTherapeutic profileVesicular traffickingGenomic analysisLipid biogenesisSecretory machineryAsexual replicationGenetic analysisReduced susceptibilityCellular traffickingApicoplast functionStrong efficacyMED6Sexual differentiationHemolytic activityDrug pipelineApicoplastKalihinolTraffickingMalaria
2022
Epitope profiling of monoclonal antibodies to the immunodominant antigen BmGPI12 of the human pathogen Babesia microti
Chand M, Choi J, Pal A, Singh P, Kumari V, Thekkiniath J, Gagnon J, Timalsina S, Gaur G, Williams S, Ledizet M, Mamoun C. Epitope profiling of monoclonal antibodies to the immunodominant antigen BmGPI12 of the human pathogen Babesia microti. Frontiers In Cellular And Infection Microbiology 2022, 12: 1039197. PMID: 36506011, PMCID: PMC9732259, DOI: 10.3389/fcimb.2022.1039197.Peer-Reviewed Original ResearchConceptsMonoclonal antibodiesAntigen detection assaysMajor immunogenic determinantMost clinical casesReliable biomarkersAntibody combinationsImmunogenic determinantsIntraerythrocytic life cycleClinical casesUnique epitopesBabesia microtiEpitope profilingHuman babesiosisTick-borne diseasesSignificant riseSerological profilingPlasma samplesAntibodiesSerological characterizationProtozoan parasitePublic healthInfectionAntigenDiseaseMammalian hostsBabesia duncani as a Model Organism to Study the Development, Virulence, and Drug Susceptibility of Intraerythrocytic Parasites In Vitro and In Vivo
Pal AC, Renard I, Singh P, Vydyam P, Chiu JE, Pou S, Winter RW, Dodean R, Frueh L, Nilsen AC, Riscoe MK, Doggett JS, Mamoun C. Babesia duncani as a Model Organism to Study the Development, Virulence, and Drug Susceptibility of Intraerythrocytic Parasites In Vitro and In Vivo. The Journal Of Infectious Diseases 2022, 226: 1267-1275. PMID: 35512141, PMCID: PMC10233494, DOI: 10.1093/infdis/jiac181.Peer-Reviewed Original ResearchConceptsLethal infectionC3H/HeJ miceMalaria-like illnessB. duncaniMouse genetic backgroundSurvival outcomesHeJ miceSevere diseaseBabesia duncaniMouse modelDifferent mouse genetic backgroundsDrug susceptibilityBabesia microtiHuman babesiosisIntraerythrocytic parasitesUnique pathogenParasite loadMiceSpecies of BabesiaApicomplexa phylumInfectionBabesia parasitesFree merozoitesHuman erythrocytesGenetic backgroundRedesigning therapies for pantothenate kinase–associated neurodegeneration
Munshi MI, Yao SJ, Mamoun C. Redesigning therapies for pantothenate kinase–associated neurodegeneration. Journal Of Biological Chemistry 2022, 298: 101577. PMID: 35041826, PMCID: PMC8861153, DOI: 10.1016/j.jbc.2022.101577.Peer-Reviewed Original ResearchConceptsPantothenate kinase-associated neurodegenerationCellular metabolic processesMore common diseasesMetabolic processesPhysiological importancePANK2 genePantothenate kinaseCoenzyme ACoenzyme A.Rare genetic disorderCommon neurodegenerative diseaseNeurodegenerative diseasesGenetic disordersNeurodegenerationNew avenuesBiosynthesisKinaseGenesNew lightFuture investigationsCofactorMutationsCommon diseaseEnzymeAlzheimer's disease
2021
Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection
Chiu JE, Renard I, Pal AC, Singh P, Vydyam P, Thekkiniath J, Kumar M, Gihaz S, Pou S, Winter RW, Dodean R, Frueh L, Nilsen AC, Riscoe MK, Doggett JS, Mamoun C. Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection. Antimicrobial Agents And Chemotherapy 2021, 65: 10.1128/aac.00662-21. PMID: 34152821, PMCID: PMC8370247, DOI: 10.1128/aac.00662-21.Peer-Reviewed Original ResearchConceptsEndochin-like quinolonesLethal infectionBlood-borne diseasesBlood-borne pathogensEffective therapyRelated apicomplexan parasitesExperimental therapiesLow doseMouse modelInfectious agentsHuman infectionsInfectionClinical candidatesStrong efficacyB. microtiExcellent safetyMode of actionTherapyErythrocytic developmentAtovaquoneEfficacyApicomplexan parasitesSafetyStructure-activity relationshipsParasitemiaCytochrome b Drug Resistance Mutation Decreases Babesia Fitness in the Tick Stages But Not the Mammalian Erythrocytic Cycle
Chiu JE, Renard I, George S, Pal A, Alday PH, Narasimhan S, Riscoe MK, Doggett JS, Mamoun C. Cytochrome b Drug Resistance Mutation Decreases Babesia Fitness in the Tick Stages But Not the Mammalian Erythrocytic Cycle. The Journal Of Infectious Diseases 2021, 225: 135-145. PMID: 34139755, PMCID: PMC8730496, DOI: 10.1093/infdis/jiab321.Peer-Reviewed Original ResearchConceptsMitochondrial cytochrome bParasite life cycleWild-type alleleTick vectorParasite fitnessCytochrome bMutant parasitesMutant allelesErythrocytic cycleArthropod vectorsNymphal stagesBabesia parasitesMutationsLife cycleFitnessTick stagesResistance mutationsMalaria-like illnessB. microtiAllelesDrug resistance mutationsParasitesHuman babesiosisTicksHostTick extracellular vesicles enable arthropod feeding and promote distinct outcomes of bacterial infection
Oliva Chávez AS, Wang X, Marnin L, Archer NK, Hammond HL, Carroll EEM, Shaw DK, Tully BG, Buskirk AD, Ford SL, Butler LR, Shahi P, Morozova K, Clement CC, Lawres L, Neal A, Mamoun CB, Mason KL, Hobbs BE, Scoles GA, Barry EM, Sonenshine DE, Pal U, Valenzuela JG, Sztein MB, Pasetti MF, Levin ML, Kotsyfakis M, Jay SM, Huntley JF, Miller LS, Santambrogio L, Pedra JHF. Tick extracellular vesicles enable arthropod feeding and promote distinct outcomes of bacterial infection. Nature Communications 2021, 12: 3696. PMID: 34140472, PMCID: PMC8211691, DOI: 10.1038/s41467-021-23900-8.Peer-Reviewed Original ResearchMeSH KeywordsAnaplasma phagocytophilumAnimalsArthropodsBacterial InfectionsCell LineDermacentorExtracellular VesiclesFrancisella tularensisGene OntologyHumansInflammationIntravital MicroscopyIxodesMaleMiceMice, Inbred C57BLMice, KnockoutMicroscopy, Electron, TransmissionProteomicsR-SNARE ProteinsSkinTandem Mass SpectrometryTicksT-LymphocytesVesicle-Associated Membrane Protein 2ConceptsExtracellular vesiclesBiology of arthropodsSynaptobrevin 2Pathogen Francisella tularensisMammalian hostsArthropodsVector feedingDistinct outcomesPathogen transmissionVesiclesMicrobial spreadingVector-borne diseasesFrancisella tularensisBacterial infectionsTicks DermacentorIxodes scapularisAnaplasma phagocytophilumBiologySkin immunitySnareDendritic epidermal T cellsPathogensHostT cellsTularensis
2020
Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria
Raj DK, Das Mohapatra A, Jnawali A, Zuromski J, Jha A, Cham-Kpu G, Sherman B, Rudlaff RM, Nixon CE, Hilton N, Oleinikov AV, Chesnokov O, Merritt J, Pond-Tor S, Burns L, Jolly G, Ben Mamoun C, Kabyemela E, Muehlenbachs A, Lambert L, Orr-Gonzalez S, Gnädig NF, Fidock DA, Park S, Dvorin JD, Pardi N, Weissman D, Mui BL, Tam YK, Friedman JF, Fried M, Duffy PE, Kurtis JD. Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria. Nature 2020, 582: 104-108. PMID: 32427965, PMCID: PMC7372601, DOI: 10.1038/s41586-020-2220-1.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAnimalsAntibodies, ProtozoanAntigens, ProtozoanAotidaeApoptosisCaspasesChildCohort StudiesDNA, ProtozoanEnzyme ActivationErythrocytesFemaleHumansIntercellular Signaling Peptides and ProteinsKenyaMalaria VaccinesMalaria, FalciparumMaleMiceParasitesPlasmodium falciparumProtozoan ProteinsTanzaniaTrophozoitesVacuolesConceptsTrophozoite-infected erythrocytesSevere malariaParasite antigensLongitudinal cohort studyPlasma of childrenCell deathNon-human primatesCohort studyEffective vaccineTanzanian childrenParasite densityInvasion of hepatocytesStage parasitesMalariaPlasmodium falciparumAntibodiesFalciparumKenyan adolescentsVaccineAntigenErythrocytesDeathChildrenInvasionParasites
2019
Evidence for vesicle-mediated antigen export by the human pathogen Babesia microti
Thekkiniath J, Kilian N, Lawres L, Gewirtz MA, Graham MM, Liu X, Ledizet M, Mamoun C. Evidence for vesicle-mediated antigen export by the human pathogen Babesia microti. Life Science Alliance 2019, 2: e201900382. PMID: 31196872, PMCID: PMC6572159, DOI: 10.26508/lsa.201900382.Peer-Reviewed Original ResearchConceptsApicomplexan parasitesCell fractionation studiesImmunoelectron microscopy analysisMode of secretionInvasion of erythrocytesParasite effectorsTrafficking motifsPlasma membraneExport mechanismClose relativesParasitophorous vacuoleHost erythrocyteMorphogenic changesFractionation studiesNovel mechanismHuman malariaFatal tick-borne diseaseMalaria-like illnessMouse red blood cellsParasitesAntigen exportTick-borne diseaseRed blood cellsHuman babesiosisImmunodominant antigensComparative 3D genome organization in apicomplexan parasites
Bunnik EM, Venkat A, Shao J, McGovern KE, Batugedara G, Worth D, Prudhomme J, Lapp SA, Andolina C, Ross LS, Lawres L, Brady D, Sinnis P, Nosten F, Fidock DA, Wilson EH, Tewari R, Galinski MR, Ben Mamoun C, Ay F, Le Roch KG. Comparative 3D genome organization in apicomplexan parasites. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 3183-3192. PMID: 30723152, PMCID: PMC6386730, DOI: 10.1073/pnas.1810815116.Peer-Reviewed Original ResearchConceptsGenome organizationGene expressionApicomplexan parasitesVirulence genesSpatial genome organizationPositioning of chromosomesRelated apicomplexan parasitesVirulence gene clusterClustering of centromeresHi-C experimentsStrong repressive effectHuman malaria parasiteChromosome foldingEukaryotic cellsGene familyGene clusterGenome modelGenomeGene clusteringMore virulent pathogensNuclear spaceRepressive effectGenesAntigenic variationVirulent pathogens
2018
BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection
Thekkiniath J, Mootien S, Lawres L, Perrin BA, Gewirtz M, Krause PJ, Williams S, Doggett J, Ledizet M, Mamoun C. BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection. Journal Of Clinical Microbiology 2018, 56: 10.1128/jcm.00067-18. PMID: 30093394, PMCID: PMC6156295, DOI: 10.1128/jcm.00067-18.Peer-Reviewed Original ResearchConceptsHuman babesiosisBabesia microti infectionCapture enzyme-linked immunosorbent assayAntigen capture enzyme-linked immunosorbent assayAntigen capture assayEnzyme-linked immunosorbent assayZoonotic infectious diseaseAcute infectionBlood transfusionAsymptomatic infectionMicroti infectionReal-time PCRBlood supplyAnimal reservoir hostsDonor bloodEpidemiological surveyHuman patientsImmune systemSerological assaysImmunodominant antigensInfectionInfectious diseasesIntraerythrocytic protozoan parasitePatientsImmunosorbent assay
2016
Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone
Lawres LA, Garg A, Kumar V, Bruzual I, Forquer IP, Renard I, Virji AZ, Boulard P, Rodriguez EX, Allen AJ, Pou S, Wegmann KW, Winter RW, Nilsen A, Mao J, Preston DA, Belperron AA, Bockenstedt LK, Hinrichs DJ, Riscoe MK, Doggett JS, Mamoun C. Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone. Journal Of Experimental Medicine 2016, 213: 1307-1318. PMID: 27270894, PMCID: PMC4925016, DOI: 10.1084/jem.20151519.Peer-Reviewed Original ResearchConceptsExperimental babesiosisHuman babesiosisImmunodeficient miceRadical cureELQ-334Discontinuation of therapyFuture clinical evaluationEndochin-like quinolonesVivo efficacy studiesAdverse side effectsRecrudescent parasitesMost clinical casesCombination therapyMultisystem diseaseClinical evaluationComplete clearanceCurrent treatmentDrug combinationsDrug failureSide effectsExcellent growth inhibitory activityEfficacy studiesClinical casesGrowth inhibitory activityAtovaquone
2015
Characterization of Plasmodium phosphatidylserine decarboxylase expressed in yeast and application for inhibitor screening
Choi JY, Kumar V, Pachikara N, Garg A, Lawres L, Toh J, Voelker DR, Ben Mamoun C. Characterization of Plasmodium phosphatidylserine decarboxylase expressed in yeast and application for inhibitor screening. Molecular Microbiology 2015, 99: 999-1014. PMID: 26585333, PMCID: PMC4898484, DOI: 10.1111/mmi.13280.Peer-Reviewed Original ResearchConceptsClass of enzymesDevelopment of antimicrobialsYeast genesMembrane biogenesisEukaryotic pathogensProenzyme processingMammalian cellsPhosphatidylserine decarboxylasePSD activityPhospholipid biosynthesisParasite enzymeEssential functionsGenetic studiesMetabolic analysisAmino acidsDecarboxylase enzymePhosphatidylethanolamine synthesisPosition 40Inhibitor screeningEssential roleYeastEnzymePlasmodium falciparumSuitable targetNovel class
2011
Phosphoethanolamine methyltransferases in phosphocholine biosynthesis: functions and potential for antiparasite therapy
Bobenchik AM, Augagneur Y, Hao B, Hoch JC, Mamoun C. Phosphoethanolamine methyltransferases in phosphocholine biosynthesis: functions and potential for antiparasite therapy. FEMS Microbiology Reviews 2011, 35: 609-619. PMID: 21303393, PMCID: PMC4107886, DOI: 10.1111/j.1574-6976.2011.00267.x.Peer-Reviewed Original ResearchConceptsStress-resistant plantsImportant biochemical stepHuman malaria parasiteMethyl donor SAMPhosphocholine biosynthesisN-methyltransferasesFlorida lanceletDependent methyltransferasesNuclear divisionBiochemical stepsDependent methylationBiological functionsGene expressionGenetic characterizationDevelopment of therapiesMalaria parasitesMajor phospholipidsDiverse groupEnzymeSmall moleculesPlantsAntiparasite therapyEukaryotesPhosphoethanolamineMethyltransferases
2008
Disruption of the Plasmodium falciparum PfPMT Gene Results in a Complete Loss of Phosphatidylcholine Biosynthesis via the Serine-Decarboxylase-Phosphoethanolamine-Methyltransferase Pathway and Severe Growth and Survival Defects*
Witola WH, El Bissati K, Pessi G, Xie C, Roepe PD, Mamoun CB. Disruption of the Plasmodium falciparum PfPMT Gene Results in a Complete Loss of Phosphatidylcholine Biosynthesis via the Serine-Decarboxylase-Phosphoethanolamine-Methyltransferase Pathway and Severe Growth and Survival Defects*. Journal Of Biological Chemistry 2008, 283: 27636-27643. PMID: 18694927, PMCID: PMC2562060, DOI: 10.1074/jbc.m804360200.Peer-Reviewed Original ResearchConceptsSDPM pathwayBiosynthesis of phosphatidylcholinePhosphatidylcholine biosynthesisParasite growthMajor membrane phospholipidsHuman malaria parasiteHost serineSerine decarboxylaseGenetic evidenceMethyltransferase enzymeSurvival defectGene resultsYeast cellsMethylation of phosphatidylethanolamineBiosynthesisSynthesis of phosphatidylcholineBiochemical studiesMembrane phospholipidsMalaria parasitesPlasmodium parasitesSevere growthPathwaySignificant defectsParasitesComplete loss