Pathogensis of Bacterial corneal infection
细菌性角膜感染的发病机制
基本信息
- 批准号:8288202
- 负责人:
- 金额:$ 38.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-01-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimal ModelAntibodiesApplications GrantsBacteriaBasic ScienceBindingBiological PreservationBlindnessCell LineCell membraneCell surfaceCellsClinical DataCommunitiesConjugate VaccinesCorneaCorneal InjuryCystic Fibrosis Transmembrane Conductance RegulatorEpithelial CellsEvaluationEyeEye InfectionsEye diseasesFundingGoalsHealthHost DefenseHumanImmuneImmune responseImmunityImmunizationImmunotherapeutic agentImmunotherapyIn VitroIndividualInfectionInflammationInflammatoryInflammatory ResponseInterventionKeratitisLeadLeucocidinLigandsLipopolysaccharidesMediatingMembrane LipidsMembrane MicrodomainsMicrobeModelingMolecularMusOligosaccharidesOryctolagus cuniculusOutcomePanton-Valentine leukocidinPathogenesisPathologyPatientsPolysaccharidesPreventionProteinsPseudomonas aeruginosaRegulatory T-LymphocyteResearchRoleSerumSmall Interfering RNASpecificityStaphylococcus aureusSurfaceTherapeuticTransgenic MiceTreatment EfficacyTreatment outcomeVaccinationVaccinesVirulenceVirulence FactorsVisionVisual AcuityWorkantimicrobialclinically significantcorneal epitheliumcystic fibrosis patientscytotoxicgene synthesishuman monoclonal antibodiesimprovedinjuredinsightmethicillin resistant Staphylococcus aureusmicrobialpathogenpoly-N-acetyl glucosaminepolyclonal antibodypre-clinicalpreventprophylacticreceptorresearch clinical testingresponsetissue culturetranscription factorvaccine candidate
项目摘要
DESCRIPTION (provided by applicant): The broad, long term goals of this grant application are to understand the molecular and cellular host responses to bacterial pathogens that are significant causes of corneal infection. Specifically, this application will focus on infections caused by Pseudomonas aeruginosa and Staphylococcus aureus. These two pathogens are among the most common causes of serious corneal infections. Strains of both pathogens have acquired significant means to resist antimicrobial therapies and elaborate a large armamentarium of virulence factors that contribute to corneal damage and loss of visual acuity. Therapies for these infections need to both reduce bacterial numbers and allow the host to have an adequate and helpful inflammatory response to clear pathogens without causing damage to the cornea. For P. aeruginosa, most of the bacteria infecting scratch-injured mouse eyes are found inside of cells, and entry requires binding to the cystic fibrosis transmembrane conductance regulator (CFTR). This leads to initiation of inflammation, including activation of transcription factors for pro-inflammatory genes, synthesis of the pro-inflammatory molecules, and initiation of the cellular influx, primarily composed of PMNs, that will both clear the pathogen but can also cause damage to the cornea. PMN influx is also controlled by the TH17 regulatory T cell network, which will also be investigated in these studies. To determine how CFTR coordinates inflammation, we will analyze the specific effectors produced by cells with wild-type CFTR that are infected with P. aeruginosa, compare these with cells lacking CFTR, and validate in animal models of corneal infection the role of the CFTR-dependent factors in bacterial clearance and corneal pathology. For S. aureus, the recent dramatic increase in methicillin-resistant S. aureus (MRSA), particularly strains elaborating the Pantone-Valentine leukocidin (PVL), makes this pathogen a significant concern as a cause of serious eye disease. The role of PVL, and antibody to PVL which is found commonly in normal human sera, will be examined in tissue culture and murine models of infection using isogenic S. aureus strains positive or negative for PVL expression, as well as immunizing mice with the PVL components to analyze how antibody modulates the course of infection. These studies should also be informative about the general role leukocidins have in the pathogenesis of S. aureus corneal infections. Further studies on MRSA strains will extend to the potential of a candidate vaccine for S. aureus infections, utilizing the poly-N-acetyl glucosamine (PNAG) surface polysaccharide as the active component of a conjugate vaccine, to ameliorate the consequences of infection. Active vaccination, as well as passive transfer studies using both polyclonal antibodies and a fully human monoclonal antibody, will be evaluated in the murine model of corneal injury to determine if PNAG is a rationale target for immunotherapy of S. aureus corneal infection. The proposed studies should ex- tend our insights into the mechanisms of bacterial virulence and effective host defense for corneal infections and provide pre-clinical data for vaccine approaches to S. aureus that could be highly effective. PUBLIC HEALTH RELEVANCE: Infections of the eye surface (cornea) are the most significant cause of loss of vision and visual acuity in the world. Bacterial pathogens are very important causes of these infections, and among the most common are Pseudomonas aeruginosa and Staphylococcus aureus. This application will study how these microbes cause damage to the cornea that can result in vision loss and evaluate interventions, including vaccines, that could be used to prevent or treat these infections and minimize damage to the cornea and thus to an individual's eyesight.
描述(由申请人提供):本拨款申请的广泛、长期目标是了解宿主对细菌病原体的分子和细胞反应,而细菌病原体是角膜感染的重要原因。具体来说,该应用程序将重点关注铜绿假单胞菌和金黄色葡萄球菌引起的感染。这两种病原体是严重角膜感染的最常见原因。这两种病原体的菌株已经获得了抵抗抗菌治疗的重要手段,并形成了大量的毒力因子,导致角膜损伤和视力丧失。针对这些感染的治疗需要既减少细菌数量,又要让宿主产生充分且有益的炎症反应来清除病原体,而不会对角膜造成损害。对于铜绿假单胞菌,大多数感染划伤小鼠眼睛的细菌都存在于细胞内部,并且进入需要与囊性纤维化跨膜电导调节器(CFTR)结合。这会导致炎症的发生,包括促炎基因转录因子的激活、促炎分子的合成以及主要由中性粒细胞组成的细胞流入的开始,这既会清除病原体,也会对组织造成损害。角膜。 PMN 流入也受到 TH17 调节性 T 细胞网络的控制,这些研究也将对其进行研究。为了确定 CFTR 如何协调炎症,我们将分析感染铜绿假单胞菌的野生型 CFTR 细胞产生的特异性效应器,将它们与缺乏 CFTR 的细胞进行比较,并在角膜感染的动物模型中验证 CFTR 的作用。细菌清除和角膜病理学的依赖因素。对于金黄色葡萄球菌,最近耐甲氧西林金黄色葡萄球菌(MRSA)的急剧增加,特别是产生潘通-瓦伦汀杀白细胞素(PVL)的菌株,使得这种病原体作为严重眼病的原因而受到关注。 PVL 以及在正常人血清中常见的 PVL 抗体的作用,将在组织培养和鼠感染模型中进行检查,使用 PVL 表达阳性或阴性的同基因金黄色葡萄球菌菌株,以及用 PVL 免疫小鼠分析抗体如何调节感染过程的成分。这些研究还应该提供有关杀白细胞素在金黄色葡萄球菌角膜感染发病机制中的一般作用的信息。对 MRSA 菌株的进一步研究将扩展到金黄色葡萄球菌感染候选疫苗的潜力,利用聚 N-乙酰氨基葡萄糖 (PNAG) 表面多糖作为结合疫苗的活性成分,以改善感染的后果。将在小鼠角膜损伤模型中评估主动疫苗接种以及使用多克隆抗体和全人单克隆抗体的被动转移研究,以确定 PNAG 是否是金黄色葡萄球菌角膜感染免疫治疗的合理目标。拟议的研究应扩展我们对细菌毒力机制和角膜感染有效宿主防御的认识,并为金黄色葡萄球菌疫苗的高效疫苗方法提供临床前数据。公共卫生相关性:眼睛表面(角膜)感染是世界上视力和视力丧失的最重要原因。细菌病原体是这些感染的非常重要的原因,其中最常见的是铜绿假单胞菌和金黄色葡萄球菌。该应用程序将研究这些微生物如何对角膜造成损害,从而导致视力丧失,并评估可用于预防或治疗这些感染的干预措施(包括疫苗),并最大限度地减少对角膜的损害,从而最大限度地减少对个人视力的损害。
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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Gerald B Pier其他文献
Gerald B Pier的其他文献
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Pathogenesis of P. aeruginosa corneal infection
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Pathogenesis of microbial anterior eye diseases
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