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Targeting SARS-CoV-2 induced lung immunopathology using novel genetic mouse models

Targeting SARS-CoV-2 induced lung immunopathology using novel genetic mouse models
使用新型基因小鼠模型针对 SARS-CoV-2 诱导的肺部免疫病理学
批准号:
10619617
负责人:
Ekaterina Koroleva
金额:
$19.02万
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:
未结题
起止时间:
2022-05-09 至 2025-04-30
关键词:
2019-nCoVACE2Acute Respiratory Distress SyndromeAgeAnimal ModelAntibody ResponseAntiviral AgentsBiochemicalBiological Response ModifiersBody Weight ChangesBrainCCL2 geneCCL20 geneCCL3 geneCOVID-19COVID-19 patientCOVID-19 treatmentCRISPR/Cas technologyCXCL1 geneCXCL2 geneCellsComplexConsensusCytokine ReceptorsDataDevelopmentDiseaseDisease modelDoseEnterobacteria phage P1 Cre recombinaseEpithelial CellsEquilibriumFlow CytometryGene Expression ProfilingGenerationsGeneticGoalsHistologyHost Defense MechanismHumanImmuneImmune TargetingImmune responseImmunityImmunohistochemistryInfectionInflammationInflammatoryInfluenza A Virus, H1N1 SubtypeInterleukin-6InvadedKnock-in MouseLungLung diseasesMediatingModelingMorbidity - disease rateMouse StrainsMusOrganPathologicPathologyPathway interactionsPatientsProductionProteinsProtocols documentationPublic HealthPublishingPulmonary PathologyReceptor SignalingReproducibilityResearchRespiratory DiseaseRoleSARS-CoV-2 infectionSARS-CoV-2 inhibitorSARS-CoV-2 pathogenesisSevere Acute Respiratory SyndromeSystemTestingTherapeuticTherapeutic UsesTransgenic MiceTumor Necrosis Factor ReceptorViralVirusVirus Replicationalveolar epitheliumantagonistbiosafety level 3 facilitychemokinecytokinecytokine release syndromedesigneffective therapyeffectiveness testingefficacy testingexperimental studyfeasibility testinghuman tissueimmune activationimmunopathologyin vivoinfluenza infectioninfluenzavirusinhibitorinnovationlung developmentlung injurylymphotoxin beta receptormembermortalitymouse modelnovelnovel therapeutic interventionpost SARS-CoV-2 infectionpreventpromoterreceptorsevere COVID-19sextherapeutic targettranscriptome sequencingvaccine access

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中文摘要
翻译
肺免疫病理学是与SARS-CoV-2相关的发病率和死亡率的主要原因 感染越来越多的证据表明,SARS-CoV-2相关的肺损伤不仅是由 病毒,但也通过过度生产的促炎细胞因子,称为细胞因子风暴。 尽管现有的疫苗和抗病毒药物可以预防感染,但这些策略并不特异性地 靶向免疫介导病理学。因此,将抗病毒宿主防御机制与抗病毒抗体解偶联, 由这些机制诱导的免疫病理学,代表了COVID-19的新治疗策略 治疗然而,要制定这样的战略,就必须更好地了解 使用COVID-19疾病的动物模型调节SARS-CoV-2诱导的免疫病理学至关重要。的 关键的差距是有限的治疗方法,特异性靶向免疫介导的病理, 重现人类肺部疾病的动物模型的可用性。小鼠模型实验 表达SARS-CoV-2受体的人ACE 2(hACE 2)显示病毒侵入脑, 多器官病理学伴有限肺部病理学,不能完全概括急性呼吸道疾病 严重COVID-19疾病患者的窘迫综合征。我们的持续结果表明, 图1. SARS-CoV-2诱导的光毒素β受体(LT β R)缺陷小鼠 免疫病理学我们还发现LTβR在另一模型中促进细胞因子风暴和肺损伤 呼吸道疾病流感感染本提案的目的是开发新的小鼠模型 模拟COVID-19患者的肺部疾病,并测试LT β R抑制剂阻断SARS-CoV的功效, 2-导致肺损伤。我们的中心假设是hACE 2在II型肺泡上皮细胞中的表达, 细胞是SARS-CoV-2诱导的肺部疾病所必需的,LT β R拮抗剂抑制SARS-CoV-2诱导的肺部疾病。 CoV-2诱导的肺免疫病理学。为了验证这一假设,我们提出了两个具体目标。在目标1中, 我们将使用CRISPR产生在II型肺泡上皮细胞中具有调节的hACE 2表达的小鼠, Cas9系统。我们将用SARS-CoV-2鼻内感染这些小鼠并评估肺部免疫病理学 和细胞因子表达。在目标2中,我们将测试LT β受体拮抗剂阻断SARS-CoV的有效性。 2-诱导免疫病理学我们将优化LT β R抑制剂的剂量和时间, 免疫病理学、病毒复制、细胞因子产生和保护性免疫。这一建议具有创新性 意义重大,因为它将产生新的动物模型来研究SARS-CoV-2的发病机制, 了解调节病毒诱导的免疫病理学的机制,并测试 靶向新的免疫调节剂LT β R,以抑制SARS-CoV-2诱导的免疫病理学,而不限制 保护性免疫
英文摘要
Lung immunopathology is a major cause of the morbidity and mortality associated with the SARS-CoV-2 infection. Accumulating evidence suggests that SARS-CoV-2-associated lung damage is caused not only by the virus, but also by excessive production of proinflammatory cytokines, known as cytokine storm. Although available vaccines and antiviral drugs protect against infection, these strategies do not specifically target immune-mediated pathology. Therefore, uncoupling anti-viral host defense mechanisms from the immunopathology induced by these mechanisms, represents a novel therapeutic strategy for COVID-19 treatment. However, to develop such strategies, a better understanding of the fundamental mechanisms that regulate SARS-CoV-2-induced immunopathology using animal models of COVID-19 disease is critical. The critical gap is limited therapeutic approaches that specifically target immune-mediated pathology and availability of animal models that recapitulate human lung disease. Experiments with mouse models expressing SARS-CoV-2 receptor, human ACE2 (hACE2) demonstrated virus invasion to the brain and multiple organ pathology with limited lung pathology, which does not fully recapitulate acute respiratory distress syndrome in patients with severe COVID-19 disease. Our ongoing results demonstrate that lymphotoxin beta receptor (LTR)-deficient mice are protected from SARS-CoV-2-induced immunopathology. We also found that LTβR promotes cytokine storm and lung damage in another model of respiratory disease, influenza infection. The objective of this proposal is to develop novel mouse models that mimic lung disease of COVID-19 patients and to test the efficacy of LTR inhibitor to block SARS-CoV- 2-induced lung damage. Our central hypothesis is that expression of hACE2 in type II alveolar epithelial cells is required for SARS-CoV-2 induced lung disease and that LTR antagonist inhibits SARS- CoV-2 induced lung immunopathology. To test this hypothesis, we propose two specific aims. In Aim 1, we will generate mice with regulated hACE2 expression in type II alveolar epithelial cells using CRISPR- Cas9 system. We will infect these mice intranasally with SARS-CoV-2 and evaluate lung immunopathology and cytokine expression. In Aim 2, we will test the effectiveness of LTR antagonist to block SARS-CoV- 2-induced immunopathology. We will optimize dose and timing of LTR inhibitors and evaluate lung immunopathology, viral replication, cytokine production, and protective immunity. This proposal is innovative and significant, as it will generate novel animal models to study SARS-CoV-2 pathogenesis, provide deeper understanding of the mechanisms regulating virus-induced immunopathology and test the feasibility of targeting novel immune regulator, LTR, to inhibit SARS-CoV-2 induced immunopathology without limiting protective immunity.
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Novel animal models to study organ-specific SARS-CoV-2-induced pathology
Targeting SARS-CoV-2 induced lung immunopathology using novel genetic mouse models
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