Oxidative killing of Pneumococcus
氧化杀死肺炎球菌
基本信息
- 批准号:10116271
- 负责人:
- 金额:$ 22.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AffectAirAnimal ModelAnionsAnti-Bacterial AgentsAttentionAttenuatedAutolysisAutomobile DrivingBacteriaBiologyCellsChildDataEconomic BurdenElderlyEncapsulatedEpithelial CellsFoundationsFutureGoalsHIVHumanHydrogen PeroxideImmuneImmune responseImpairmentIn VitroInfectionInnate Immune ResponseInnate Immune SystemInterventionKnowledgeLiquid substanceLungLung infectionsMediatingMeningitisMissionModelingMusNADPH OxidaseOutcomeOxidasesOxidesPathogenesisPatientsPneumococcal InfectionsPneumoniaProductionProteinsPublic HealthPublishingResearchRespirationRoleSepticemiaSourceStreptococcus pneumoniaeSystemTestingTherapeuticThiocyanatesTimeTissuesUnited States National Institutes of HealthWorkairway epitheliumairway surface liquidanti-influenzaantimicrobialapical membranebasebronchial epitheliumcell killingco-infectioncommunity acquired pneumoniadesignextracellularfightinghuman diseasehypothiocyaniteimprovedin vitro testingin vivoinfluenza infectioninfluenza pneumoniainnate immune mechanismsinnovationlung injurymicrobicidemortalitymouse modelnovelnovel therapeuticsoxidationrespiratoryrespiratory pathogenweapons
项目摘要
Streptococcus pneumoniae (Spn) is the main cause of community acquired pneumonia and
meningitis in children and the elderly, and of septicemia in HIV patients. Boosting the function of host
immune responses could offer novel intervention strategies against Spn. There is a critical gap in our
knowledge to identify new, broad range, anti-Spn mechanisms of the respiratory innate immune system.
Bronchial epithelial cells (BEC) are the primary responders to Spn infection. BECs orchestrate an
oxidative extracellular antimicrobial system present in the airway surface liquid consisting of the protein
lactoperoxidase (LPO), the thiocyanate anion (SCN-) and hydrogen peroxide (H2O2). LPO oxidizes SCN-
using H2O2 into microbicidal hypothiocyanite (OSCN-). Dual oxidase 1 (Duox1), an NADPH oxidase
protein highly expressed in the apical membrane of BECs, is the H2O2 source for the antimicrobial action
of LPO. Our preliminary result show that the Duox1/LPO-based system efficiently kills several strains of
Spn in different experimental systems. Our long-term goal is to determine whether the Duox1/LPO/SCN-
antibacterial system could be manipulated in Spn infection for therapeutic purposes in humans. The
objective of this proposal is to establish the anti-Spn role of the Duox1/LPO-based oxidative mechanism.
Based on preliminary data our central hypothesis is that the Duox1/H2O2/LPO/SCN- system kills Spn
bacteria in a strain-independent manner, attenuates infection and associated tissue damage in a mouse
model of Spn lung infection. To test this hypothesis, our specific aims are to determine the mechanism
of Spn killing by Duox1/LPO in vitro, to establish the in vivo role of Duox1 in Spn killing, and to explore
whether therapeutic manipulation of the Duox1/LPO-based system attenuates Spn pneumonia in an
animal model. The rationale for the proposed research is that we need to characterize how powerful the
Duox1/LPO-based system is in fighting Spn to explore its therapeutical potential in humans in the future.
It is anticipated that our aims will yield the following expected outcomes: 1) identification of the
antibacterial mechanism of the Duox1/LPO-based system against Spn, 2) establishing the in vivo
relevance of Duox1 in Spn infection; and 3) providing essential results on the therapeutic potential of the
Duox1/LPO-based mechanism to attenuate Spn lung infection. Our innovative work shows that a unique
antimicrobial system is powerful in killing Spn and explores a novel, nontraditional immune mechanism
for its potential to be used against a major lung pathogen. In summary, our proposal will have a positive
impact in the fields of airway epithelial and Spn biology, and general antibacterial innate immune
responses by identifying Duox1 and LPO, as a novel, crucial, innate immune weapons of the respiratory
innate immune system against Spn.
肺炎链球菌(Spn)是社区获得性肺炎和
儿童和老年人的脑膜炎,艾滋病毒患者的败血症。提升主机的功能
免疫反应可以提供针对Spn的新的干预策略。我们有一个严重的差距
识别新的、广泛的、抗Spn的呼吸系统先天免疫系统机制的知识。
支气管上皮细胞(BEC)是Spn感染的主要应答细胞。BEC协调
存在于由蛋白质组成的呼吸道表面液体中的氧化胞外抗菌系统
乳过氧化物酶(LPO)、硫氰酸根阴离子(SCN-)和过氧化氢(H2O2)。LPO氧化SCN-
利用过氧化氢对次硫氰酸盐(OSCN-)进行杀菌。NADPH酶--双氧化酶1(Duox1)
在内皮细胞顶膜高表达的蛋白质是过氧化氢抗菌作用的来源。
LPO的。我们的初步结果表明,基于Duox1/LPO的系统有效地杀死了几个菌株
不同实验体系中的SPN。我们的长期目标是确定Duox1/LPO/SCN-
在人类的Spn感染中,抗菌系统可以被操纵用于治疗目的。这个
本研究的目的是建立基于Duox1/LPO的氧化机制的抗Spn作用。
根据初步数据,我们的中心假设是Duox1/H_2O_2/LPO/SCN-系统杀死Spn
细菌以不依赖菌株的方式减轻小鼠的感染和相关的组织损伤
Spn肺部感染模型。为了检验这一假设,我们的具体目标是确定机制
Duox1/LPO对Spn的体外杀伤作用,探讨Duox1在体内对Spn的杀伤作用
基于Duox1/LPO系统的治疗操作是否能减轻Spn肺炎
动物模型。提出这项研究的理由是,我们需要刻画出
基于Duox1/LPO的系统正在与Spn对抗,以探索其未来在人类中的治疗潜力。
预计我们的目标将产生以下预期结果:1)确定
基于Duox1/LPO的抗Spn系统的抗菌机制2)体内实验研究
Duox1与Spn感染的相关性;以及3)提供关于Duox1治疗潜力的基本结果
基于Duox1/LPO的抗Spn肺部感染机制我们的创新工作表明,一种独特的
抗菌系统对Spn具有强大的杀灭作用,并探索了一种新的、非传统的免疫机制
因为它有可能被用来对抗一种主要的肺部病原体。总而言之,我们的建议将产生积极的影响
在呼吸道上皮和Spn生物学领域的影响,以及一般抗菌天然免疫
识别Duox1和LPO作为呼吸道的一种新的、至关重要的先天免疫武器的反应
针对Spn的天然免疫系统。
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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{{ truncateString('Balazs Rada', 18)}}的其他基金
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金黄色葡萄球菌感染与囊性纤维化自身免疫的关系
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金黄色葡萄球菌感染与囊性纤维化自身免疫的关系
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10353431 - 财政年份:2021
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Dual oxidase and lactoperoxidase in influenza infection
流感感染中的双氧化酶和乳过氧化物酶
- 批准号:
10328261 - 财政年份:2020
- 资助金额:
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Dual oxidase and lactoperoxidase in influenza infection
流感感染中的双氧化酶和乳过氧化物酶
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10556348 - 财政年份:2020
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