Chitin and chitinases in SARS-CoV-2 infection
SARS-CoV-2 感染中的几丁质和几丁质酶
基本信息
- 批准号:10742004
- 负责人:
- 金额:$ 19.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVACE2AcuteAddressAffectAirAirborne Particulate MatterAntibodiesAreaAttenuatedBindingBiological MarkersCOVID-19COVID-19 mortalityCOVID-19 pandemicCOVID-19 severityCardiovascular DiseasesCessation of lifeChitinChitinaseChronicClinicalCoughingDataDepositionDiabetes MellitusDictyopteraDiseaseDisease OutcomeDisease ProgressionDyspneaElderlyEnvironmentEnvironmental ExposureEnvironmental Risk FactorEpithelial CellsEpitheliumExhibitsExposure toFeverFunctional disorderHealthHouse Dust Mite AllergensHousingHumanHypertensionImmune responseImpairmentInfectionInflammationInflammation MediatorsInflammatoryInhalationInjuryIntegration Host FactorsLinkLong-Term EffectsLungLung diseasesLung immune responseMediatingMoldsMolecularMusPathologicPathologyPathway interactionsPatientsPatternPhasePhysiologyPolymersPolysaccharidesPopulationPost-Acute Sequelae of SARS-CoV-2 InfectionProcessPulmonary FibrosisPulmonary PathologyRaceRecombinantsRecoveryReporterRespiratory DiseaseRespiratory FailureRiskRoleSARS-CoV-2 infectionSARS-CoV-2 pathogenesisSeveritiesSeverity of illnessTMPRSS2 geneTestingTherapeuticTranslationsUnited StatesViralViral Respiratory Tract InfectionVirus Diseasesage relatedairway epitheliumbiomarker identificationcytokine release syndromedemographicsenzyme therapyepithelial injuryethnic minority populationfibrotic lung diseasegain of functionglobal healthillness lengthimprovedinnovationloss of functionmortalitymouse modelnew therapeutic targetnovelnovel therapeutic interventionpandemic diseaseparticlepatient stratificationpost SARS-CoV-2 infectionpredictive markerreceptorresponserestorationsevere COVID-19therapeutic targettransgene expressiontreatment strategy
项目摘要
ABSTRACT
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and resultant coronavirus disease 2019
(COVID-19) has caused a global health crisis, surpassing 100 million infections in the United States. SARS-
CoV-2 infections range from asymptomatic to respiratory failure and death, and can result in an array of long-
term effects collectively referred to as post-acute sequelae of SARS-CoV-2 infection (PASC). The
pathobiological mechanisms and environmental factors underlying the intensity and duration of these effects
remain unclear, but a range of chronic lung impairments that resemble complications associated with age-related
pulmonary fibrosis have been documented in severe COVID-19, suggesting that environmental drivers
implicated in pulmonary fibrosis may also influence the course of SARS-CoV-2 infection and PASC. We have
identified the environmental constituent chitin as a candidate environmental driver of persistent SARS-CoV-2-
induced disease, consistent with its previously described role in pulmonary fibrosis. Our preliminary studies show
that chitin spontaneously accumulates in the lungs of SARS-CoV-2-infected mice, and is accompanied by
alterations in the expression patterns of the major lung chitinase, AMCase, suggesting that chitin-chitinase
interactions may contribute to SARS-CoV-2 pathogenesis. In comparison with wild-type (WT) controls, mice that
genetically lack AMCase exhibit exacerbated lung pathology after infection with SARS-CoV-2, implicating chitin
and chitinases in the pathologic sequelae that occur during the recovery phase. Thus, we hypothesize that
environmental chitin can drive COVID-19 severity, epithelial dysregulation, and disease persistence, and that
epithelial chitinases attenuate this process by degrading chitin. In this project, we leverage recently developed
mouse models of SARS-CoV-2 infection and chitin exposure to delineate a host-environmental interaction that
may contribute to persistent lung impairments following SARS-CoV-2 infection. We will test our hypothesis by
addressing two Aims: (1) determine the influence of environmental chitin on the severity and persistence of lung
pathology after SARS-CoV-2 infection, and (2) define the role of mammalian chitinases in SARS-CoV-2 infection
and persistent lung disease. Understanding how environmental chitin influences long-lasting pathologic
responses after SARS-CoV-2 infection may lead to the identification of new biomarkers and therapeutic targets
associated with differential disease outcomes in COVID-19 and PASC.
摘要
严重急性呼吸综合征冠状病毒2(SARS-CoV-2)及其引发的冠状病毒病2019
新冠肺炎(Alipay)引发了一场全球健康危机,美国感染人数已超过1亿。非典--
CoV-2感染范围从无症状到呼吸衰竭和死亡,并可导致一系列长期的
长期效应统称为SARS-CoV-2感染的急性后遗症(PASC)。这个
这些影响的强度和持续时间背后的病理生物学机制和环境因素
尚不清楚,但一系列慢性肺损伤类似于与年龄相关的并发症
肺纤维化已经在严重的新冠肺炎中被记录下来,这表明环境驱动因素
参与肺纤维化也可能影响SARS-CoV-2感染和PASC的病程。我们有
确定环境成分甲壳素是持续SARS-CoV-2的候选环境驱动因素-
诱导性疾病,与之前描述的其在肺纤维化中的作用一致。我们的初步研究表明
这种甲壳素自发地积聚在感染SARS-CoV-2的小鼠的肺部,并伴随着
肺主要几丁质酶AMCase表达模式的变化提示几丁质-几丁质酶
相互作用可能在SARS-CoV-2的发病机制中起作用。与野生型(WT)对照组相比,
遗传性缺乏AMCase显示感染SARS-CoV-2后肺部病理加重,与甲壳素有关
以及在恢复期出现的病理后遗症中的几丁质酶。因此,我们假设
环境甲壳素可以推动新冠肺炎的严重性、上皮细胞失调和疾病持久性,而且
上皮性几丁质酶通过降解几丁质来减弱这一过程。在这个项目中,我们利用最近开发的
SARS-CoV-2感染和甲壳素暴露的小鼠模型描述宿主与环境的相互作用
可能导致SARS-CoV-2感染后的持续性肺损伤。我们将通过以下方式验证我们的假设
解决两个目标:(1)确定环境甲壳素对肺的严重性和持久性的影响
SARS-CoV-2感染后的病理,以及(2)确定哺乳动物几丁质酶在SARS-CoV-2感染中的作用
和持续性肺部疾病。了解环境甲壳素如何影响长期病理
SARS-CoV-2感染后的反应可能导致新的生物标志物和治疗靶点的确定
与新冠肺炎和PASC的不同疾病结局相关。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Steven Van Dyken其他文献
Steven Van Dyken的其他文献
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