Streptococcus pneumoniae ocular pathogenesis and therapy

肺炎链球菌眼部发病机制及治疗

• 批准号: 8035361
• 负责人: MARY E MARQUART
• 金额: $ 24.05万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035361
• 关键词: Alternative Therapies; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Award; Bacteria; Bacterial Eye Infections; Binding; Cells; Cholesterol; Cicatrix; Clinical; Complement Activation; Conjunctivitis; Cornea; Cytolysis; Data; Development; Disease; Endophthalmitis; Epithelial Cells; Eye; Eye Infections; Goals; Group Meetings; Human; Immune; Immune Sera; Immune response; Immunoglobulin Isotypes; Immunology; In Vitro; Infection; Inflammation; Inflammatory Response; Keratitis; Knowledge; Laboratories; Lead; Mediating; Meningitis; Microbiology; Modeling; Morbidity - disease rate; Ophthalmology; Organism; Oryctolagus cuniculus; Otitis Media; Parents; Pathogenesis; Patients; Phenotype; Pneumococcal Infections; Pneumonia; Polysaccharides; Prevention; Production; Public Health; Publishing; Reagent; Research; Research Personnel; Resistance; Role; Site; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; Symptoms; Testing; Tissues; Topical application; Vaccination; Vaccines; Virulence; Virulence Factors; Vision; Work; base; capsule; corneal epithelium; corneal scar; design; direct application; effective therapy; killings; meetings; mutant; neutrophil; novel; pathogen; prevent; programs; success; therapy development; vision science

DESCRIPTION: Streptococcus pneumoniae is a major cause of bacterial keratitis. Pneumococcal keratitis causes damage that can result in irreversible corneal scarring. The corneal damage seen in pneumococcal keratitis has been attributed mainly to bacterial virulence factors that stimulate an intense host response. Important to pneumococcal keratitis is the production of pneumolysin, a virulence factor capable of cell lysis as well as the activation of complement. In non-ocular infections, the production of pneumolysin is not sufficient to achieve virulence; the organism must also produce a polysaccharide capsule. The role of the capsule in keratitis or other ocular infections has not been established and preliminary data from this laboratory suggests that the capsule may not contribute to ocular virulence. This point is significant because vaccination of patients has been suggested as a means to prevent pneumococcal ocular infections. The research proposed is designed to develop means to limit the damage associated with pneumococcal keratitis. This research consists of using new therapies directed toward the virulence factors responsible for protecting the organism and stimulating the damaging inflammatory response. The immediate aims are to: 1) determine if the capsule is a virulence factor in keratitis, a study that could show that the cornea, unlike vascularized body sites, is susceptible to infection by unencapsulated strains; 2) determine if the inhibition of pneumolysin by topical application of a molecule that inhibits its binding to cells will provide protection against inflammation to the infected cornea, a possibility that is supported by preliminary studies; and 3) determine if antibody to pneumolysin can be used actively or passively to limit or prevent the ability of this molecule to induce inflammation with tissue damaging effects. From a public health perspective, bacteria including pneumococcus are becoming increasingly resistant to antibiotics. The development of alternative and novel therapies for bacterial eye infections will help to prevent scarring and loss of the eye.

描述：肺炎链球菌是细菌性角膜炎的主要原因。肺炎球菌角膜炎造成的损害可能导致不可逆的角膜疤痕。肺炎球菌角膜炎中出现的角膜损伤主要归因于刺激强烈宿主反应的细菌毒力因子。对于肺炎球菌性角膜炎来说，重要的是肺炎球菌溶血素的产生，这是一种能够裂解细胞并激活补体的毒力因子。在非眼部感染中，肺炎球菌溶血素的产生不足以达到毒力；该生物体还必须产生多糖胶囊。胶囊在角膜炎或其他眼部感染中的作用尚未确定，该实验室的初步数据表明胶囊可能不会导致眼部毒力。这一点很重要，因为已建议对患者进行疫苗接种作为预防肺炎球菌眼部感染的一种手段。拟议的研究旨在开发限制肺炎球菌角膜炎相关损害的方法。这项研究包括使用针对负责保护机体和刺激破坏性炎症反应的毒力因子的新疗法。直接目标是：1）确定荚膜是否是角膜炎的毒力因子，这项研究可能表明角膜与血管化的身体部位不同，容易受到未包膜菌株的感染； 2) 确定通过局部应用抑制肺炎球菌溶血素与细胞结合的分子来抑制肺炎球菌溶血素是否会为受感染的角膜提供针对炎症的保护，初步研究支持了这种可能性； 3)确定是否可以主动或被动使用肺炎球菌溶血素抗体来限制或防止该分子诱导具有组织损伤作用的炎症的能力。从公共卫生的角度来看，包括肺炎球菌在内的细菌对抗生素的耐药性越来越强。针对细菌性眼部感染的替代疗法和新型疗法的开发将有助于防止眼睛留下疤痕和丧失。

项目成果

Active Immunization with Pneumolysin versus 23-Valent Polysaccharide Vaccine for Streptococcus pneumoniae Keratitis.

• DOI: 10.1167/iovs.10-6968
• 发表时间: 2011-11
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Erin W. Norcross;M. Sanders;Quincy C. Moore;S. Taylor;Nathan A. Tullos;Rhonda R. Caston;S. N. Dixon;M. Nahm;R. Burton;H. Thompson;L. McDaniel;M. Marquart

Development of a Streptococcus pneumoniae keratitis model in mice.

小鼠肺炎链球菌角膜炎模型的建立。

• DOI: 10.1159/000229028
• 发表时间: 2009
• 期刊: Ophthalmic research
• 影响因子: 2.1
• 作者: Moore3rd,QuincyC;McCormick,ClareC;Norcross,ErinW;Onwubiko,Chinwendu;Sanders,MelissaE;Fratkin,Jonathan;McDaniel,LarryS;O'Callaghan,RichardJ;Marquart,MaryE
• 通讯作者: Marquart,MaryE

Immunization with pneumolysin protects against both retinal and global damage caused by Streptococcus pneumoniae endophthalmitis.

肺炎链球菌溶血素免疫可防止肺炎链球菌眼内炎引起的视网膜和整体损伤。

• DOI: 10.1089/jop.2010.0077
• 发表时间: 2010
• 期刊: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics
• 作者: Sanders,MelissaE;Norcross,ErinW;Moore3rd,QuincyC;Fratkin,Jonathan;Thompson,Hilary;Marquart,MaryE
• 通讯作者: Marquart,MaryE

The cholesterol-dependent cytolysin pneumolysin from Streptococcus pneumoniae binds to lipid raft microdomains in human corneal epithelial cells.

来自肺炎链球菌的胆固醇依赖性溶细胞素肺炎球菌溶血素与人角膜上皮细胞中的脂筏微区结合。

• DOI: 10.1371/journal.pone.0061300
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Taylor,SidneyD;Sanders,MelissaE;Tullos,NathanA;Stray,StephenJ;Norcross,ErinW;McDaniel,LarryS;Marquart,MaryE
• 通讯作者: Marquart,MaryE

Pathogenesis of A Clinical Ocular Strain of Streptococcus pneumoniae and the Interaction of Pneumolysin with Corneal Cells.

肺炎链球菌临床眼部菌株的发病机制以及肺炎链球菌溶血素与角膜细胞的相互作用。

• DOI: 10.4172/2155-9597.1000108
• 发表时间: 2011
• 期刊: Journal of bacteriology & parasitology
• 作者: Norcross,ErinW;Sanders,MelissaE;Moore3rd,QuincyC;Marquart,MaryE
• 通讯作者: Marquart,MaryE