Host Responses to the Pore-Forming Toxin Listeriolysin O
宿主对成孔毒素李斯特菌溶血素 O 的反应
基本信息
- 批准号:10376220
- 负责人:
- 金额:$ 67.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAntigen PresentationAntigen-Presenting CellsAntigensBacteriaBindingCalciumCalcium ChannelCancer VaccinesCathepsinsCell DeathCell SurvivalCell membraneCell physiologyCell surfaceCellsCholesterolCommunicable DiseasesComplexConsequentialismCytolysinsCytoskeletal ProteinsCytosolDataDendritic CellsDevelopmentDiseaseEpithelial CellsEventExcisionExocytosisExposure toFamilyFluorescence MicroscopyGenesGoalsGram-Positive BacteriaHistocompatibility Antigens Class IIHomeostasisHospitalizationImageImmuneImmune responseImmunityIn VitroInfectionInflammasomeInflammatoryInjuryInnate Immune ResponseKnowledgeLaboratoriesLengthLibrariesLifeLife Cycle StagesListeriaListeria monocytogenesListeria monocytogenes hlyA proteinListeriosisLysosomesMediatingMembraneMicroscopyMindModelingMyopathyNeurodegenerative DisordersPathogenesisPathologyPathway interactionsPerforationPhagosomesPlasma CellsPlayProcessPropertyProtein Kinase CProteinsProteomicsPublishingRecombinantsReportingResolutionRoleSignal TransductionSmall Interfering RNASpeedStructure-Activity RelationshipT cell responseT-LymphocyteTestingTherapeutic InterventionTimeToxinToxoidsVaccinesVacuoleVariantVirulenceVirulence FactorsWorkanti-cancerantimicrobialbasecathepsin Kcell typefoodborne illnessfoodborne pathogenin vivomacrophagemolecular assembly/self assemblynovelnovel therapeutic interventionpathogenprematurerational designrecruitrepairedresponsescreeningspatiotemporaltraffickingvaccine developmentvoltage
项目摘要
Summary
Listeria monocytogenes is a facultative intracellular pathogen responsible for the life-threatening disease
listeriosis. Although Lm produces numerous virulence factors, the secreted pore-forming toxin LLO is
indispensable for pathogenesis. LLO is secreted at all stages of the Listeria intracellular life cycle and binds to
cholesterol to form transmembrane pores. This virulence factor perforates the membrane of the Listeria-
containing endocytic vacuoles to release the bacterium into its replicative niche, the cytosol. It was recently
established that LLO also perforates the host cell plasma membrane, which promotes host cell invasion. It
remains to elucidate how infected cells maintain viability despite perforation of their plasma membranes and how
this low-grade perforation impacts the course of Listeria infection. The work performed in Aim 1 will establish
novel mechanisms that maintain viability of infected cells despite perforation of their plasma membranes by LLO.
Preliminary studies, via screening of a large siRNA library, led to the identification of novel families of host
proteins that were not previously known to repair the plasma membrane of toxin-perforated cells. The Aim 1
studies will establish the mechanisms of action of these novel proteins. Specifically, they will determine the role
plasma membrane depolarization plays in organizing calcium-dependent lysosome exocytosis, leading to the
release of cytoprotective cathepsins on the cell surface. Aim 1 will also establish a new role for the septins, a
family of cytoskeletal proteins, in plasma membrane repair. These studies will employ high-speed and super-
resolution microscopy to analyze the molecular assemblies that orchestrate plasma membrane repair. The Aim
2 studies will establish the impact of plasma membrane perforation by LLO on Listeria intracellular survival and
the innate immune response of antigen-presenting cells. We showed that transient plasma membrane
perforation by LLO triggers Ca2+ influx-dependent activation of conventional PKCs on the endosomal network, a
signaling event that is critical for Listeria phagosome escape. Aim 2 will identify the PKCs effectors by SILAC-
based quantitative proteomic approach and how they contribute to the release of Listeria into the cytosol. Plasma
membrane perforation also causes K+ efflux, which is known to activate the NLRP3 inflammasome. Aim 2 will
dissect the role of low-grade plasma membrane perforation in the maturation of antigen presenting cells to
enhance T cell immunity, in vitro and in vivo. This work is expected to broadly impact the development of vaccines
and novel therapeutic strategies for a wide range of diseases in which pore-forming toxins are employed by
pathogens.
摘要
单核细胞增多性李斯特菌是一种引起这种危及生命的疾病的兼性细胞内病原体。
李斯特菌病。虽然LM产生许多毒力因子,但分泌的致孔毒素LLO是
是发病过程中不可缺少的。LIO在李斯特菌细胞内生命周期的所有阶段都会分泌,并与
胆固醇形成跨膜孔。这种毒力因子穿透李斯特氏菌的细胞膜-
含有内吞液泡,以将细菌释放到其复制的小生境,即胞浆中。那是最近的事
证实LLO还穿透宿主细胞质膜,促进宿主细胞侵袭。它
仍然需要阐明受感染的细胞如何在质膜穿孔的情况下保持活性,以及如何
这种低度穿孔会影响李斯特菌的感染过程。在目标1中完成的工作将建立
尽管LLO使受感染细胞的质膜穿孔,但仍能维持其活性的新机制。
通过筛选大的siRNA文库,初步研究导致了新的寄主家族的鉴定
以前未知的修复毒素穿孔细胞质膜的蛋白质。目标1
研究将确定这些新蛋白质的作用机制。具体地说,他们将确定
质膜去极化在组织钙依赖的溶酶体胞吐中起作用,导致
细胞表面细胞保护性组织蛋白的释放。目标1还将为Septins建立一个新的角色,一个
细胞骨架蛋白家族,参与质膜修复。这些研究将采用高速和超
分辨率显微镜分析协调质膜修复的分子组装。其目的是
2项研究将确定LLO质膜穿孔对李斯特菌细胞内存活和
抗原提呈细胞的先天免疫反应。我们证明了瞬变质膜
LLO穿孔触发传统PKCs在内体网络上的钙内流激活,a
信号事件是李斯特氏菌吞噬小体逃逸的关键。目标2将通过SILAC识别PKCS效应器-
基于定量蛋白质组学的方法以及它们如何促进李斯特菌释放到细胞质中。电浆
膜穿孔还会导致K+外流,从而激活NLRP3炎症体。目标2将
解剖低度质膜穿孔在抗原提呈细胞成熟中的作用
增强体内和体外T细胞免疫功能。这项工作有望对疫苗的发展产生广泛影响
以及对一系列疾病的新治疗策略,在这些疾病中,形成毛孔的毒素由
病原体。
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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Amal O Amer其他文献
Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and thrombosis
Caspase-4/11 通过促进炎症和血栓形成而加剧 SARS-CoV-2 感染的疾病严重程度
- DOI:
10.1101/2021.09.24.461743 - 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
Mostafa Eltobgy;Ashley N. Zani;A. Kenney;Shady Z K Estfanous;Eunsoo Kim;Asmaa Badr;Cierra Carafice;Kylene P. Daily;Owen Whitham;Maciej Pietrzak;Amy Webb;Jeffrey Kawahara;Adrian C. Eddy;Parker J Denz;Mijia Lu;K. Mahesh;M. Peeples;Jianrong Li;Jian Zhu;Jianwen Que;Richard T Robinson;Oscar Rosas Mejia;R. Rayner;Luanne Hall;S. Seveau;M. Gavrilin;Andrea Tedeschi;Santiago Partida;Frank Roberto;Emily A. Hemann;Eman Abdelrazik;Adriana Forero;S. Nimjee;P. Boyaka;E. Cormet;J. Yount;Amal O Amer - 通讯作者:
Amal O Amer
Amal O Amer的其他文献
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{{ truncateString('Amal O Amer', 18)}}的其他基金
Mechanisms of lung and cardiac pathology in SARS-CoV-2 infections
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10445615 - 财政年份:2022
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宿主对成孔毒素李斯特菌溶血素 O 的反应
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10625363 - 财政年份:2021
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10310743 - 财政年份:2021
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