Featured Publications
The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice
Ullah I, Beaudoin-Bussières G, Symmes K, Cloutier M, Ducas E, Tauzin A, Laumaea A, Grunst M, Dionne K, Richard J, Bégin P, Mothes W, Kumar P, Bazin R, Finzi A, Uchil P. The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice. Cell Reports Medicine 2022, 4: 100893. PMID: 36584683, PMCID: PMC9799175, DOI: 10.1016/j.xcrm.2022.100893.Peer-Reviewed Original ResearchConceptsCOVID-19 convalescent plasmaFc effector functionsSARS-CoV-2 controlFc effector activityInnate immune cellsCCP efficacyHACE2 miceConvalescent plasmaImmunoglobulin levelsPlasma therapyImmune cellsTreatment efficacyDelays mortalityIgG fractionFc functionLow neutralizingTherapySecond lineMortalityMicePlasma contributesEfficacyFC activityProphylaxisIgGIn vivo imaging of retrovirus infection reveals a role for Siglec-1/CD169 in multiple routes of transmission
Haugh KA, Ladinsky MS, Ullah I, Stone HM, Pi R, Gilardet A, Grunst MW, Kumar P, Bjorkman PJ, Mothes W, Uchil PD. In vivo imaging of retrovirus infection reveals a role for Siglec-1/CD169 in multiple routes of transmission. ELife 2021, 10: e64179. PMID: 34223819, PMCID: PMC8298093, DOI: 10.7554/elife.64179.Peer-Reviewed Original ResearchConceptsSentinel macrophagesSiglec-1/CD169Immune surveillance functionCommon host factorMesenteric sacsPeyer's patchesGastrointestinal tractOral routeReporter virusRetrovirus transmissionRetrovirus infectionFrontline cellsRetroviral pathogenesisHost factorsBioluminescence imagingVirus entryIncoming virusInfectionRetrovirus life cycleCD169Early eventsMacrophagesMultiscale imaging approachVirusSurveillance functionLive imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy
Ullah I, Prévost J, Ladinsky MS, Stone H, Lu M, Anand SP, Beaudoin-Bussières G, Symmes K, Benlarbi M, Ding S, Gasser R, Fink C, Chen Y, Tauzin A, Goyette G, Bourassa C, Medjahed H, Mack M, Chung K, Wilen CB, Dekaban GA, Dikeakos JD, Bruce EA, Kaufmann DE, Stamatatos L, McGuire AT, Richard J, Pazgier M, Bjorkman PJ, Mothes W, Finzi A, Kumar P, Uchil PD. Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy. Immunity 2021, 54: 2143-2158.e15. PMID: 34453881, PMCID: PMC8372518, DOI: 10.1016/j.immuni.2021.08.015.Peer-Reviewed Original ResearchConceptsCOVID-19 convalescent subjectsSARS-CoV-2 infectionBioluminescence imagingK18-hACE2 miceLive bioluminescence imagingNatural killer cellsFc effector functionsSARS-CoV-2Convalescent subjectsKiller cellsPotent NAbsImmune protectionInflammatory responseEffector functionsNasal cavityNaB treatmentOptimal efficacyFc functionDepletion studiesMiceNAbsCOVID-19Direct neutralizationInfectionAntibodiesA Protective Role for the Lectin CD169/Siglec-1 against a Pathogenic Murine Retrovirus
Uchil PD, Pi R, Haugh KA, Ladinsky MS, Ventura JD, Barrett BS, Santiago ML, Bjorkman PJ, Kassiotis G, Sewald X, Mothes W. A Protective Role for the Lectin CD169/Siglec-1 against a Pathogenic Murine Retrovirus. Cell Host & Microbe 2018, 25: 87-100.e10. PMID: 30595553, PMCID: PMC6331384, DOI: 10.1016/j.chom.2018.11.011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD8-Positive T-LymphocytesCell ProliferationDendritic CellsDisease Models, AnimalErythroblastsFemaleInterferon Type ILectinsLymph NodesMacrophagesMaleMiceMice, Inbred BALB CMice, Inbred C57BLProtective AgentsRetroviridaeRetroviridae InfectionsSialic Acid Binding Ig-like Lectin 1SpleenT-Lymphocytes, CytotoxicViral LoadConceptsCD169/SiglecEffective cytotoxic T lymphocyte (CTL) responseProtective roleCytotoxic T lymphocyte responsesLymph node infectionT lymphocyte responsesHigh viral loadSusceptible mouse strainsMarginal zone metallophilic macrophagesPermissive lymphocytesCytotoxic CD8Lymphocyte responsesViral loadSubcapsular sinusComplex infectionMurine modelViral disseminationMetallophilic macrophagesRed pulpCell responsesSystemic spreadMouse strainsPathogenesisCells 1CD169Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection
Sewald X, Ladinsky MS, Uchil PD, Beloor J, Pi R, Herrmann C, Motamedi N, Murooka TT, Brehm MA, Greiner DL, Shultz LD, Mempel TR, Bjorkman PJ, Kumar P, Mothes W. Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection. Science 2015, 350: 563-567. PMID: 26429886, PMCID: PMC4651917, DOI: 10.1126/science.aab2749.Peer-Reviewed Original ResearchConceptsHuman immunodeficiency virusLymph nodesMurine leukemia virusCD169/SiglecSecondary lymphoid tissuesPermissive lymphocytesDendritic cellsImmunodeficiency virusSynaptic contactsLymphoid tissueRobust infectionVirological synapsesI-type lectinsRetroviral spreadViral spreadUninfected cellsInfectionLeukemia virusVirusMacrophagesCellsRetrovirusesCell-cell contactCD169LymphocytesTRIM E3 Ligases Interfere with Early and Late Stages of the Retroviral Life Cycle
Uchil PD, Quinlan BD, Chan WT, Luna JM, Mothes W. TRIM E3 Ligases Interfere with Early and Late Stages of the Retroviral Life Cycle. PLOS Pathogens 2008, 4: e16. PMID: 18248090, PMCID: PMC2222954, DOI: 10.1371/journal.ppat.0040016.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Retroviral AgentsApoptosisAvian leukosis virusCell SurvivalGag Gene Products, Human Immunodeficiency VirusGene Expression Regulation, ViralGene SilencingHeLa CellsHIVHost-Pathogen InteractionsHumansLeukemia Virus, MurineMiceRetroviridaeUbiquitin-Protein LigasesVirus ReplicationConceptsHuman immunodeficiency virus-1Viral life cycleMurine leukemia virusAvian leukosis virusImmunodeficiency virus-1Antiretroviral activityHIV entryTRIM proteinsAntiviral activityLater stagesVirus 1TRIM11Virus releaseViral releaseLeukemia virusRetroviral life cycleHEK293 cellsLeukosis virusVirusComprehensive screenReleaseCellsProteinTRIM15 is a focal adhesion protein that regulates focal adhesion disassembly
Uchil PD, Pawliczek T, Reynolds TD, Ding S, Hinz A, Munro JB, Huang F, Floyd RW, Yang H, Hamilton WL, Bewersdorf J, Xiong Y, Calderwood DA, Mothes W. TRIM15 is a focal adhesion protein that regulates focal adhesion disassembly. Journal Of Cell Science 2014, 127: 3928-3942. PMID: 25015296, PMCID: PMC4163643, DOI: 10.1242/jcs.143537.Peer-Reviewed Original ResearchConceptsFocal adhesion proteinsFocal adhesionsCell migrationAdhesion proteinsMulti-adaptor proteinTripartite motif (TRIM) protein familyFocal adhesion dynamicsFocal adhesion turnoverFocal adhesion componentsCoiled-coil domainImpaired cell migrationII-independent mannerLD2 motifAdhesion turnoverActin cytoskeletonProtein familyAdhesion dynamicsCellular functionsDynamic turnoverMacromolecular complexesRegulatory componentsFocal contactsAdhesion componentsExtracellular matrixTRIM15
2024
Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid
Papini C, Ullah I, Ranjan A, Zhang S, Wu Q, Spasov K, Zhang C, Mothes W, Crawford J, Lindenbach B, Uchil P, Kumar P, Jorgensen W, Anderson K. Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2320713121. PMID: 38621119, PMCID: PMC11046628, DOI: 10.1073/pnas.2320713121.Peer-Reviewed Original ResearchConceptsDirect-acting antiviralsSARS-CoV-2Lack of off-target effectsIn vitro pharmacological profileTreatment of patientsDevelopment of severe symptomsPharmacological propertiesDrug-drug interactionsSARS-CoV-2 infectionProof-of-concept studySARS-CoV-2 M<sup>pro</sup>.Combination regimenImmunocompromised patientsLead compoundsSARS-CoV-2 main proteaseOral doseActive drugTreat infectionsPharmacological profileSARS-CoV-2 MPotential preclinical candidateOff-target effectsPatientsComplete recoveryCapsule formulation
2023
PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
Xu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 2023, 619: 819-827. PMID: 37438530, PMCID: PMC10371867, DOI: 10.1038/s41586-023-06322-y.Peer-Reviewed Original ResearchConceptsC-terminal β-barrel domainSpike-mediated fusionCell-autonomous defenseLarge-scale exome sequencingΒ-barrel domainGenome-wide CRISPRSARS-CoV-2 infectionHost cell cytosolScramblase activityPhospholipid scramblaseLive SARS-CoV-2 infectionHuman lung epitheliumPLSCR1SARS-CoV-2 USASingle-molecule switchingSARS-CoV-2 variantsExome sequencingHuman populationRestriction factorsViral RNANew SARS-CoV-2 variantsSARS-CoV-2Robust activityLung epitheliumDefense factors
2022
A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection
Beaudoin-Bussières G, Chen Y, Ullah I, Prévost J, Tolbert WD, Symmes K, Ding S, Benlarbi M, Gong SY, Tauzin A, Gasser R, Chatterjee D, Vézina D, Goyette G, Richard J, Zhou F, Stamatatos L, McGuire AT, Charest H, Roger M, Pozharski E, Kumar P, Mothes W, Uchil PD, Pazgier M, Finzi A. A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection. Cell Reports 2022, 38: 110368. PMID: 35123652, PMCID: PMC8786652, DOI: 10.1016/j.celrep.2022.110368.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, NeutralizingAntibodies, ViralAntibody-Dependent Cell CytotoxicityCOVID-19COVID-19 SerotherapyDisease Models, AnimalEpitopesHumansImmunization, PassiveImmunoglobulin Fab FragmentsImmunoglobulin Fc FragmentsMiceProtein BindingProtein ConformationSARS-CoV-2Spike Glycoprotein, Coronavirus
2019
Longitudinal bioluminescent imaging of HIV-1 infection during antiretroviral therapy and treatment interruption in humanized mice
Ventura JD, Beloor J, Allen E, Zhang T, Haugh KA, Uchil PD, Ochsenbauer C, Kieffer C, Kumar P, Hope TJ, Mothes W. Longitudinal bioluminescent imaging of HIV-1 infection during antiretroviral therapy and treatment interruption in humanized mice. PLOS Pathogens 2019, 15: e1008161. PMID: 31805155, PMCID: PMC6917343, DOI: 10.1371/journal.ppat.1008161.Peer-Reviewed Original ResearchConceptsHIV-1 infectionHumanized miceCombination antiretroviral therapy regimenViral spreadHIV-1 infection dynamicsNon-invasive bioluminescentAntiretroviral therapy regimenHIV-1 reporterSame lymphoid tissuesInfected cell populationCART withdrawalInfection recrudescenceAntiretroviral therapyTreatment interruptionTherapy regimenLymphoid tissueInfection dynamicsART treatmentBioluminescent imagingInfectionViral infection dynamicsInfected cellsCell populationsMiceBioluminescent signalMurine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice
Pi R, Iwasaki A, Sewald X, Mothes W, Uchil PD. Murine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice. Journal Of Virology 2019, 93: 10.1128/jvi.00930-19. PMID: 31434732, PMCID: PMC6803250, DOI: 10.1128/jvi.00930-19.Peer-Reviewed Original ResearchConceptsPopliteal lymph nodesFriend murine leukemia virusInnate immune sensing pathwaysToll-like receptor 7Viral spreadMurine leukemia virusCell-deficient miceType I interferon responseWild-type miceCell populationsType I interferonLeukemia virusRobust virus replicationI interferon responseAntiviral intervention strategiesInfected cell typesSentinel macrophagesAdoptive transferCell typesLymph nodesReceptor 7Virus infectionInnate sensingB cellsI interferonTransfection of Mammalian Cells with Calcium Phosphate-DNA Coprecipitates.
Kumar P, Nagarajan A, Uchil PD. Transfection of Mammalian Cells with Calcium Phosphate-DNA Coprecipitates. Cold Spring Harbor Protocols 2019, 2019: pdb.top096255. PMID: 31575800, DOI: 10.1101/pdb.top096255.Peer-Reviewed Original ResearchCalcium Phosphate-Mediated Transfection of Eukaryotic Cells with Plasmid DNAs.
Kumar P, Nagarajan A, Uchil PD. Calcium Phosphate-Mediated Transfection of Eukaryotic Cells with Plasmid DNAs. Cold Spring Harbor Protocols 2019, 2019: pdb.prot095430. PMID: 31575793, DOI: 10.1101/pdb.prot095430.Peer-Reviewed Original Research
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
2015
TRIM5 Retroviral Restriction Activity Correlates with the Ability To Induce Innate Immune Signaling
Lascano J, Uchil PD, Mothes W, Luban J. TRIM5 Retroviral Restriction Activity Correlates with the Ability To Induce Innate Immune Signaling. Journal Of Virology 2015, 90: 308-316. PMID: 26468522, PMCID: PMC4702541, DOI: 10.1128/jvi.02496-15.Peer-Reviewed Original ResearchConceptsInnate immune signalingImmune signalingHIV-1 transductionHIV-1 restrictionAP-1 signalingViral nucleic acidsAP-1Retroviral capsid latticeAP-1 activationRestriction activityPast infectionProtein cyclophilin ARetrovirus infectionTRIM5Cyclophilin AActivity correlatesInfectionTRIM5 geneReverse transcriptionRetroviral transductionSignalingHost cell nucleusRetroviral capsidActivationTRIM family
2011
Targeted Disruption of the CCR5 Gene in Human Hematopoietic Stem Cells Stimulated by Peptide Nucleic Acids
Schleifman EB, Bindra R, Leif J, del Campo J, Rogers FA, Uchil P, Kutsch O, Shultz LD, Kumar P, Greiner DL, Glazer PM. Targeted Disruption of the CCR5 Gene in Human Hematopoietic Stem Cells Stimulated by Peptide Nucleic Acids. Cell Chemical Biology 2011, 18: 1189-1198. PMID: 21944757, PMCID: PMC3183429, DOI: 10.1016/j.chembiol.2011.07.010.Peer-Reviewed Original ResearchConceptsHematopoietic stem cellsHIV-1CCR5 geneHIV-1-infected individualsHIV-1 infectionGene modificationHIV-1 entryCCR5-Delta32 mutationImmune system functionStem cellsCCR5 knockoutMonths posttransplantationChemokine receptorsHuman hematopoietic stem cellsTherapeutic strategiesSubsequent engraftmentGenome modificationProtein levelsHuman cellsTargeted disruptionCCR5Peptide nucleic acidInfectionNucleic acidsCells
2008
Murine Leukemia Virus Spreading in Mice Impaired in the Biogenesis of Secretory Lysosomes and Ca2+-Regulated Exocytosis
Chan WT, Sherer NM, Uchil PD, Novak EK, Swank RT, Mothes W. Murine Leukemia Virus Spreading in Mice Impaired in the Biogenesis of Secretory Lysosomes and Ca2+-Regulated Exocytosis. PLOS ONE 2008, 3: e2713. PMID: 18629000, PMCID: PMC2443282, DOI: 10.1371/journal.pone.0002713.Peer-Reviewed Original ResearchConceptsMurine leukemia virusMultivesicular bodiesPlasma membraneHermansky-Pudlak syndromeLysosome related organellesFunctional AP-3Moloney murine leukemia virusMVB pathwaySynaptotagmin VIILeukemia virusRelated organellesLysosome fusionAP-3Secretory lysosomesMost mutant miceMLV replicationWild-type miceCellular levelBiogenesisModerate reductionEssential roleVirus releaseRelease pathwayMutant miceImmunological alterations