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
2019年严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)及其导致的冠状病毒疾病
(COVID-19)已造成全球健康危机,美国感染人数超过1亿。SARS-
CoV-2感染的范围从无症状到呼吸衰竭和死亡,并可导致一系列长期的-
术语效应统称为SARS-CoV-2感染后急性后遗症(PASC)。的
这些影响的强度和持续时间的病理生物学机制和环境因素
目前尚不清楚,但一系列慢性肺损伤,类似于与年龄相关的并发症,
在严重的COVID-19中已经记录了肺纤维化,这表明环境驱动因素
与肺纤维化有关也可能影响SARS-CoV-2感染和PASC的过程。我们有
确定了环境成分几丁质作为持续性SARS-CoV-2的候选环境驱动因素,
诱导的疾病,与其先前描述的在肺纤维化中的作用一致。我们的初步研究显示
甲壳素在SARS-CoV-2感染小鼠的肺部自发积累,并伴随着
主要肺几丁质酶AMCase表达模式的改变,表明几丁质-几丁质酶
相互作用可能有助于SARS-CoV-2的发病机制。与野生型(WT)对照相比,
在感染SARS-CoV-2后,遗传上缺乏AMCase的患者表现出加重的肺部病理学,
以及在恢复期发生的病理后遗症中的几丁质酶。因此,我们假设,
环境甲壳素可以驱动COVID-19的严重程度、上皮失调和疾病持续,
上皮几丁质酶通过降解几丁质来减弱该过程。在这个项目中,我们利用最近开发的
SARS-CoV-2感染和几丁质暴露的小鼠模型,以描述宿主-环境相互作用,
可能导致SARS-CoV-2感染后持续性肺损伤。我们将测试我们的假设,
目的:(1)确定环境甲壳素对肺损伤的严重程度和持续性的影响
SARS-CoV-2感染后的病理学,以及(2)确定哺乳动物几丁质酶在SARS-CoV-2感染中的作用
和持续性肺病了解环境几丁质如何影响长期病理
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鉴定
与COVID-19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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