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Understanding the microbial requirements for colonization and immunogenicity of commensal bacteria at the ocular surface

了解眼表共生细菌定植和免疫原性的微生物要求

基本信息

批准号：
10628040
负责人：
ANTHONY J ST LEGER
金额：
$ 39.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10628040
关键词：
Address Adhesions Affect Antigen Presentation Area Automobile Driving Bacteria Bacterial Genes Candida albicans Candidate Disease Gene Caring Cell Wall Cells Clinical Comparative Genomic Analysis Complement Cornea Corynebacterium Data Dendritic Cells Development Disease Economic Burden Eye Eye Development Eye diseases Formulation Foundations Future Genes Genomics Glaucoma Goals Health Hour Human IL17 gene Immune Immune response Immunity In Vitro Infection Inflammation Interleukin-1 beta Knowledge Laboratories Libraries Ligation Mucous Membrane Mus Mutate Mutation Nature Neutrophil Infiltration Pathogenicity Pathway interactions Peripheral Blood Mononuclear Cell Persons Phenotype Play Probiotics Production Proteins Pseudomonas aeruginosa Public Health Research Rest Role Signal Transduction Source Symbiosis T-Cell Receptor Testing Time Translating Universities Visual impairment antimicrobial clinically relevant commensal bacteria cost host-microbe interactions immunogenicity in vivo insight microbial microbial products microbiome mutant novel novel therapeutics ocular microbiome ocular surface ocular surface disease prevent probiotic therapy response screening side effect symptom treatment virtual γδ T cells

项目摘要

Abstract Ocular surface disease has an astounding economic burden of over $12 billion per year for treatment. While current standards of care only treat symptoms rather than address the cause(s) of disease, recent data suggest that manipulation of the microbiome may be a potential avenue to treat and/or prevent disease. Recently, an ocular commensal bacterium, Corynebacterium mastitidis (C. mast), was identified and shown to protect the ocular surface from infection with C. albicans and P. aeruginosa. Despite this beneficial immunity, there is still a need to understand the microbial factors that govern ocular colonization and ability to stimulate the host immune response. The foundation of the proposed studies was built upon preliminary data acquired from genomically and phenotypically screening over 30 clinically relevant isolates of Corynebacterium spp. and nearly 2000 transposon mutants of C. mast. Specifically, the first aim will identify microbial factor(s) that govern ocular colonization by testing eight C. mast mutants that were predicted to lack an ability to colonize the eye. The second aim will discover microbial factor(s) that stimulate host immunity by assessing immunogenicity, in vitro and in vivo, of nine different C. mast mutants that were predicted to have a limited ability to induce immune responses. The third aim will mechanistically define how ocular commensal bacteria stimulate the human immune response. As outlined, the proposed studies will provide multiple layers of information beneficial to ocular health. First, Aims 1 and 2 will provide the identity of specific genes that play a critical role in the nature of an ocular commensal, which will allow future studies to better distinguish true ocular commensals from other bacteria that are temporarily introduced to the eye. These aims will also shed light on genes that may be desirable in the formulation of genetically modified ocular bacteria or ocular probiotics. Finally, Aim 3 will provide valuable knowledge on a virtually unknown area, which is the human immune response against Corynebacterium spp. Because Corynebacteria are fairly ubiquitous throughout the body, these data will have far-reaching implications for not only the eye, but throughout the rest of the body. In sum, the proposed studies will form the foundation for the future development of ocular probiotics to treat eye diseases.

摘要眼表疾病每年有超过120亿美元的惊人经济负担，治疗虽然目前的护理标准只治疗症状，而不是解决原因（S）最近的数据表明，操纵微生物组可能是一种潜在的途径，以治疗和/或预防疾病。最近，一种眼内细菌，棒状杆菌， Mastiobacterium（C.肥大），被鉴定并显示保护眼表面免受C. 白色念珠菌和铜绿假单胞菌。尽管有这种有益的免疫力，控制眼部定植和刺激宿主免疫能力的微生物因素反应拟议研究的基础是建立在从以下方面获得的初步数据之上：基因组和表型筛选超过30个临床相关的棒状杆菌分离株 spp.和近2000个C.桅杆具体而言，第一个目标将确定通过测试八种C.肥大突变体被预测缺乏在眼睛中定居的能力。第二个目标是发现微生物因素其通过评估9种不同C. 肥大细胞突变体被预测具有有限的诱导免疫应答的能力。第三 aim将从机理上定义眼内细菌如何刺激人体免疫反应如前所述，拟议的研究将提供多层有益的信息，眼睛健康。首先，目标1和2将提供发挥关键作用的特定基因的身份。作用的性质，眼神经，这将使未来的研究，以更好地区分真正的暂时进入眼睛的其他细菌引起的眼部炎症。这些目标还将揭示在基因修饰的眼用制剂中可能需要的基因，细菌或眼益生菌。最后，目标3将提供关于一个几乎未知的区域，其是针对棒状杆菌属的人免疫应答。因为棒状杆菌在人体内相当普遍，这些数据将具有深远意义。不仅对眼睛，而且对身体的其他部位都有影响。总之，拟议的研究将为未来开发眼用益生菌治疗眼部疾病奠定基础。