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Elucidating the role of RXRA in the myeloid lineage in post-infectious basal ganglia encephalitis

Elucidating the role of RXRA in the myeloid lineage in post-infectious basal ganglia encephalitis
阐明 RXRA 在感染后基底节脑炎骨髓谱系中的作用
批准号:
10574727
负责人:
Dritan Agalliu
金额:
$44.19万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-15 至 2024-08-31
关键词:
2019-nCoVAcuteAgeAnimal ModelAnimalsAntibodiesAntigen PresentationAutoantibodiesAutoimmuneAutoimmune DiseasesAutopsyBacterial InfectionsBasal GangliaBehavioralBehavioral AssayBioinformaticsBiopsyBlood - brain barrier anatomyBrainCD3 AntigensCNS autoimmune diseaseCellsChildChildhoodDiseaseEncephalitisEthnic OriginExcitatory SynapseFamilyFrequenciesFunctional disorderGenesGeneticGenomic DNAHumanImmuneImmune responseImmunofluorescence ImmunologicImmunotherapyImpairmentIn VitroInfectionInfectious AgentInfiltrationInnate Immune ResponseLinkLymphocyteMediatingMedical centerMessenger RNAMicrogliaMissense MutationMovementMusMutationMycoplasmaMyelogenousMyeloid CellsNeuraxisNeuronsNonsense MutationNosePathogenesisPathologicPathologyPatientsPediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus InfectionsPediatric HospitalsPhagocytesPhagocytosisPhiladelphiaPhysiologicalPlayPositron-Emission TomographyPredisposing FactorProductionProteinsRXRA geneRaceRecurrenceReportingRiskRisk FactorsRodentRodent ModelRoleSeizuresStreptococcus pyogenesSydenham ChoreaSymptomsSynapsesSyndromeT-LymphocyteTestingTherapeuticUniversitiesValidationVirusadaptive immune responseadaptive immunityclinical efficacycohortcytokinediagnostic strategydisorder riskexome sequencingfightinggene environment interactiongenetic risk factorgenetic varianthuman diseasehuman modelin vivoinduced pluripotent stem cellinsightloss of functionmacrophagemouse modelneural circuitneuroinflammationneuronal circuitryneuropsychiatric disorderneuropsychiatryneurovascular injurynovelnovel therapeuticspediatric patientspotential biomarkerreceptorresponserisk variantsexsingle-cell RNA sequencingtreatment strategy

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英文摘要
PROJECT SUMMARY Childhood infections with Streptococcus pyogenes (Group A Streptococcus; GAS) are associated with basal ganglia encephalitis (BGE) sequelae that present with either movement [Sydenham’s chorea (SC)] or psychiatric [Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS)] symptoms. Human and animal studies have shown that aberrant cellular (Th17 lymphocytes) and humoral (autoantibodies) adaptive immune responses, generated normally to fight recurrent S. pyogenes infections, target the brain and elicit neurovascular damage, antibody entry into the brain, neuroinflammation (microglial activation and macrophage infiltration) and neural circuit dysfunction. However, not all children develop post- infectious BGE despite frequent GAS infections suggesting the presence of genetic risk factors that predispose them to develop disease. Through whole-exome sequencing of genomic DNA from 82 patients and 146 controls followed by bioinformatics analysis, we have identified candidate genetic variants in ~20 genes that are likely associated with disease risk for post-infectious BGE. One of the top BGE risk genes, RXRA (encoding for Retinoid X Receptor Alpha), is a key regulator of both innate and adaptive immune responses. We have found that Rxra mRNA and proteins levels are upregulated in activated microglia and infiltrating macrophages in the brain after recurrent intranasal GAS infections in mice. Here, we will test the hypothesis that RXRA, identified by whole-exome sequencing, regulates several innate immune responses in the myeloid lineage (microglia and macrophages) ranging from activation, antigen presentation, cytokine production and phagocytosis, that are critical for both neurovascular damage and neuronal circuit dysfunction in the brain after recurrent GAS infections. We have generated mice lacking Rxra function in the myeloid lineage (microglia and macrophages). For our first objective, we will test the requirement of Rxra in microglial/macrophages for their activation, antigen presentation, cytokine production and phagocytosis in vivo using PET imaging, single cell RNA sequencing and validation in our mouse model for post-infectious BGE. In parallel, we will perform in vitro studies with the human microglia cells, carrying the nonsense mutations in the RXRA gene identified in SC/PANDAS/PANS patients, to test activation and phagocytic ability following GAS exposure. For our second objective, we will examine the consequences of eliminating Rxra function in the myeloid cell for neurovascular damage (i.e. blood-brain barrier dysfunction), elimination of excitatory synapses and neuronal circuitry dysfunction using single cell RNA sequencing studies, pathological, physiological and behavioral assays after recurrent intranasal GAS infections in control or myeloid-specific Rxra deficient mice. These proof-of-principle studies have the potential to uncover novel mechanisms of disease pathogenesis and develop potential biomarkers or new therapeutics to assist in diagnostic and treatment strategies for families, of which there are currently few with limited clinical efficacy.
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