Deciphering the cellular signals emanating from Staphylococcus aureus LukAB interaction with host-receptor that result in immune cell death
破译金黄色葡萄球菌 LukAB 与宿主受体相互作用发出的细胞信号,导致免疫细胞死亡
基本信息
- 批准号:9377482
- 负责人:
- 金额:$ 0.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-01 至 2017-07-03
- 项目状态:已结题
- 来源:
- 关键词:Adaptive Immune SystemAddressAmino Acid SequenceAmino AcidsAntibody ResponseBindingBiochemistryBiological AssayCell DeathCell LineCellsCessation of lifeChildClinicalCommunitiesComplexCytolysisCytoplasmic TailDataDendritic CellsDevelopmentDimerizationDiseaseExhibitsFoundationsFutureG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGoalsHealthcareHumanITGAM geneITGB2 geneImmuneImmune systemImmunologicsIn VitroInfectionIntegration Host FactorsIntegrinsKnock-outKnowledgeLeukocytesLifeMacrophage-1 AntigenMammalian GeneticsMediatingMethodsModelingNaturePathogenesisPathway interactionsPhagocytesPhagocytosisPneumoniaProductionProtein Tyrosine KinaseRecurrenceReportingResearchRoleSerumSeveritiesSignal TransductionSignaling MoleculeSignaling ProteinStaphylococcus aureusSurfaceTailTestingToxinTreatment EfficacyUnited StatesVariantViralVirulenceVirulence Factorsbacterial geneticscell killingcell typeclinically relevantcohortcytokinecytotoxiccytotoxicitydimereffective therapyexperimental studygain of functiongenetic variantin vivoinhibitor/antagonistinsightkillingsknock-downmacrophagemethicillin resistant Staphylococcus aureusmonocytemutantneutrophilnovelpathogenreceptorresponseskin abscesssmall hairpin RNAsmall molecule inhibitortreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
In the United States Staphylococcus aureus infections are highly prevalent, both in healthcare settings and
within the community. These infections range in severity from recurrent skin abscesses to life-threatening
necrotizing pneumonias. A clear understanding of how S. aureus is able to subvert the host immune system
is necessary in order to develop effective therapeutic approaches. Important factors contributing to S.
aureus virulence are the bi-component pore forming toxins (B-PFTs). B-PFT subunits assemble on the
surface of host cells and form oligomeric pores that ultimately result in cellular death. Leukocidin AB,
LukAB, is the most recently identified B-PFT and kills primary human neutrophils, monocytes, macrophages
and dendritic cells. Among S. aureus B-PFTs, LukAB contains the most amino-acid divergence, is the only
toxin known to enhance S. aureus survival upon phagocytosis by human neutrophils, is the only toxin
isolated as a dimer, and is the only B-PFT that uses a host integrin as a receptor (specifically CD11b, a
component of the CD11b/CD18 integrin). Allelic variants of LukAB are also found in clinical isolates,
although their functional role is unknown. Additionally, the mechanistic details of how LukAB induces cell
death remain largely unknown. As such, the primary goal of this proposal is to identify the cellular signals
emanating from LukAB interaction with host receptor that result in immune cell death. Experiments
described in this application seek to (i) determine the role of the cytoplasmic tail of CD11b, and associated
tyrosine kinases, toward LukAB-mediated cell death in human monocytes and (ii) determine the contribution
of LukAB-allelic variants to immune cell response and lysis. Methods in the proposed experiments involve
immunological biochemistry, mammalian and bacterial genetics, and in vitro and ex vivo cytotoxicity assays.
Fully addressing these questions will provide a greater understating of the mechanistic details for an
important S. aureus virulence factor and provide the necessary foundation for future development of specific
inhibitors to LukAB-mediated cell death.
项目总结/摘要
在美国,金黄色葡萄球菌感染在医疗保健环境中和
在社区内。这些感染的严重程度从复发性皮肤脓肿到危及生命
坏死性肺炎清楚地了解S。金黄色葡萄球菌能够破坏宿主的免疫系统
为了开发有效的治疗方法是必要的。影响S.
金黄色葡萄球菌毒力是双组分成孔毒素(B-PFT)。B-PFT亚基组装在
在宿主细胞表面形成寡聚孔,最终导致细胞死亡。杀白细胞素AB,
LukAB是最近发现的B-PFT,可杀死原代人中性粒细胞、单核细胞、巨噬细胞
和树突状细胞。在S. aureus B-PFTs中,LukAB含有最多的氨基酸差异,是唯一的
已知能增强S.金黄色葡萄球菌在被人类嗜中性粒细胞吞噬后存活,是唯一的毒素
作为二聚体分离,并且是唯一使用宿主整联蛋白作为受体的B-PFT(特别是CD 11b,
CD 11b/CD 18整合素)。在临床分离株中也发现了LukAB的等位基因变体,
尽管它们的功能作用是未知的。此外,LukAB如何诱导细胞凋亡的机制细节
死亡情况仍然不明。因此,本提案的主要目标是识别蜂窝信号
源自LukAB与宿主受体的相互作用,导致免疫细胞死亡。实验
本申请中描述的方法试图(i)确定CD 11b的胞质尾区的作用,以及相关的
酪氨酸激酶对人单核细胞中LukAB介导的细胞死亡的作用,以及(ii)确定
LukAB等位基因变体对免疫细胞应答和溶解的影响。所提出的实验中的方法包括
免疫生物化学、哺乳动物和细菌遗传学以及体外和离体细胞毒性测定。
充分解决这些问题将提供一个更大的理解的机制细节,
重要的S。为今后开发特异性的金黄色葡萄球菌毒力因子提供必要的基础
LukAB介导的细胞死亡的抑制剂。
项目成果
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