Control of parasite invasion by a microneme protein complex conserved in Apicomplexans
顶复门中保守的微线体蛋白复合物控制寄生虫入侵
基本信息
- 批准号:10302285
- 负责人:
- 金额:$ 48.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsApicalApicomplexaBacterial AdhesinsBindingBiochemicalBiological AssayBiotinCRISPR screenCarbohydratesCategoriesCell Membrane PermeabilityCell Surface ProteinsCell surfaceCellsChemicalsClustered Regularly Interspaced Short Palindromic RepeatsComplementComplexConserved SequenceCryptosporidiosisCryptosporidiumDependenceDevelopmentDiseaseDistantEtiologyEventFaceFibroblastsFluorescence-Activated Cell SortingGenesGeneticHumanImpairmentInfectionInfectious AgentIntegration Host FactorsLigaseLinkLipidsLivestockLytic PhaseMalariaMediatingModelingMolecularNamesNational Institute of Allergy and Infectious DiseaseOrganellesParasite ControlParasitesPathogenesisPhenotypePlasmodiumPlasmodium falciparumPlayProcessProtein SecretionProtein translocationProteinsRegulationSchemeSignal TransductionStructureSurfaceSymptomsSystemTissuesToxoplasma gondiiToxoplasmosisUrsidae Familybasebiodefensecell motilitycrosslinkexperimental studyextracellularfitnessgenome wide screennovelnovel therapeuticsopportunistic pathogenparasite invasionparasitismpreservationprophylacticprotein complexrhoptrytrafficking
项目摘要
7. PROJECT SUMMARY/ABSTRACT
Apicomplexan parasites include the etiologic agents of many widespread infections of humans and livestock,
such as malaria and toxoplasmosis. These diseases are caused by destruction of the host tissues in which the
parasites replicate. Because apicomplexans only replicate inside host cells, the process of invasion is critical to
their survival and pathogenesis. Invasion is mediated by the release of proteins from specialized secretory
organelles at the apical end of the parasite, the micronemes and rhoptries. Microneme proteins include
adhesins that support parasite motility and are therefore secreted as soon as parasites emerge from replication
and start migrating towards new host cells to infect. Rhoptries, by contrast, secrete their contents only upon
host cell recognition once parasites have committed to invasion. Evidence suggests that the release of rhoptry
contents depends on the prior secretion of microneme proteins; however, the molecular events that link these
two processes are unknown. Based on a genome-wide screen in the model apicomplexan Toxoplasma gondii,
our lab recently identified a conserved microneme protein necessary for invasion of human cells, which we
named CLAMP. Our preliminary studies show that CLAMP is necessary for rhoptry secretion and stably
associates with two microneme proteins: SPATR, which was previously implicated in invasion, and an
uncharacterized protein we call CLIP. We hypothesize that these interactions represent a novel invasion
complex necessary for rhoptry protein secretion. Our first aim is to compare the functions of CLAMP,
SPATR, and CLIP; investigate how they oligomerize; and elucidate the relationship between complex
formation and rhoptry secretion. In our second aim, we will identify and characterize host and parasite proteins
that interact with the CLAMP invasion complex. Finally, our third aim will take an unbiased look at the host cell
factors that stimulate rhoptry protein secretion, which may intersect with the CLAMP complex to regulate this
key step in apicomplexan invasion. Based on the conservation of the parasite proteins involved, we expect that
the principles uncovered will be generalizable to the phylum and broadly inform our understanding of these
infectious agents.
7.项目总结/摘要
顶复门寄生虫包括许多广泛的人类和牲畜感染的病原体,
例如疟疾和弓形虫病。这些疾病是由宿主组织的破坏引起的,
寄生虫复制。由于顶复门只在宿主细胞内复制,因此入侵过程对宿主细胞的生长至关重要。
他们的生存和发病机制。入侵是由特定的分泌细胞释放蛋白质介导的。
寄生虫顶端的细胞器,微丝和棒状体。蛋白质组包括
支持寄生虫运动并因此在寄生虫复制后立即分泌的粘附素
并开始向新的宿主细胞迁移以进行感染。相比之下,棒状体只在
一旦寄生虫入侵,宿主细胞识别。有证据表明释放棒状体
含量取决于微线体蛋白的先前分泌;然而,连接这些微线体蛋白的分子事件
两个过程是未知的。基于在模型顶复门弓形虫中的全基因组筛选,
我们的实验室最近发现了一种保守的微线体蛋白,它是入侵人类细胞所必需的,我们
名为CLAMP。我们的初步研究表明CLAMP是棒状体分泌所必需的,
与两种微线体蛋白相关:SPATR,以前与入侵有关,
我们称之为CLIP的未知蛋白质。我们假设这些相互作用代表了一种新的入侵
棒状体蛋白分泌所必需的复合物。我们的第一个目的是比较CLAMP的功能,
SPATR和CLIP;研究它们如何寡聚化;并阐明复合物之间的关系
形成和棒状体分泌。在我们的第二个目标,我们将确定和表征宿主和寄生虫蛋白质
与CLAMP入侵复合体相互作用。最后,我们的第三个目标是对宿主细胞进行公正的观察
刺激棒状体蛋白分泌的因子,其可能与CLAMP复合物交叉以调节这种分泌。
是顶复体入侵的关键步骤基于所涉及的寄生虫蛋白的保守性,我们预计,
所揭示的原理将普遍适用于动物门,并广泛地告知我们对这些原理的理解。
传染源
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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Sebastian Lourido其他文献
Sebastian Lourido的其他文献
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{{ truncateString('Sebastian Lourido', 18)}}的其他基金
Development and maintenance of chronic toxoplasmosis
慢性弓形虫病的发展和维持
- 批准号:
10181740 - 财政年份:2021
- 资助金额:
$ 48.75万 - 项目类别:
Development and maintenance of chronic toxoplasmosis
慢性弓形虫病的发展和维持
- 批准号:
10579245 - 财政年份:2021
- 资助金额:
$ 48.75万 - 项目类别:
Development and maintenance of chronic toxoplasmosis
慢性弓形虫病的发展和维持
- 批准号:
10374148 - 财政年份:2021
- 资助金额:
$ 48.75万 - 项目类别:
Control of parasite invasion by a microneme protein complex conserved in Apicomplexans
顶复门中保守的微线体蛋白复合物控制寄生虫入侵
- 批准号:
10531601 - 财政年份:2019
- 资助金额:
$ 48.75万 - 项目类别:
Control of parasite invasion by a microneme protein complex conserved in Apicomplexans
顶复门中保守的微线体蛋白复合物控制寄生虫入侵
- 批准号:
9886387 - 财政年份:2019
- 资助金额:
$ 48.75万 - 项目类别:
Control of parasite invasion by a microneme protein complex conserved in Apicomplexans
顶复门中保守的微线体蛋白复合物控制寄生虫入侵
- 批准号:
10062827 - 财政年份:2019
- 资助金额:
$ 48.75万 - 项目类别:
Identification of novel Toxoplasma genes involved in host-parasite interactions
鉴定参与宿主-寄生虫相互作用的新弓形虫基因
- 批准号:
9203042 - 财政年份:2016
- 资助金额:
$ 48.75万 - 项目类别:
Dissecting essential signaling pathways in apicomplexan parasites
剖析顶端复门寄生虫的重要信号通路
- 批准号:
8609230 - 财政年份:2013
- 资助金额:
$ 48.75万 - 项目类别:
Dissecting essential signaling pathways in apicomplexan parasites
剖析顶端复门寄生虫的重要信号通路
- 批准号:
8737992 - 财政年份:2013
- 资助金额:
$ 48.75万 - 项目类别:
Dissecting essential signaling pathways in apicomplexan parasites
剖析顶端复门寄生虫的重要信号通路
- 批准号:
9349383 - 财政年份:2013
- 资助金额:
$ 48.75万 - 项目类别:
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