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.

抽象的眼表疾病每年的经济负担惊人的经济负担超过120亿美元治疗。虽然目前的护理标准仅治疗症状，而不是解决原因关于疾病，最近的数据表明，对微生物组的操纵可能是潜在的途径治疗和/或预防疾病。最近，眼球细菌，Corynebacterium 鉴定并证明了Mastitidis（C.桅杆），以保护眼表面免受C的感染。白色念珠菌和铜绿假单胞菌。尽管这种有益的免疫力，仍然需要了解控制眼殖和刺激宿主免疫的能力的微生物因子回复。拟议研究的基础是基于从中获取的初步数据在基因组和表型上筛查30次临床相关的小杆菌分离株 spp。以及近2000个桅杆的转座子突变体。具体而言，第一个目标将确定微生物因子通过测试八个肥大突变体来控制眼定定殖的微生物因子预计缺乏殖民眼睛的能力。第二个目标将发现微生物因子通过评估九个不同的C. 预计肥大突变体具有有限的诱导免疫反应能力。第三 AIM将机械地定义眼部共生细菌如何刺激人类免疫回复。如概述，拟议的研究将提供多层信息有益对眼部健康。首先，目标1和2将提供具有关键的特定基因的身份在眼部的性质中的作用，这将使以后的研究能够更好地区分真实来自其他细菌的眼部分子被暂时引入眼睛。这些目标还将阐明在基因修饰的眼上可能需要的基因细菌或眼益生菌。最后，AIM 3将对几乎未知的有价值的知识提供宝贵的知识面积是针对Corynebacterium spp的人类免疫反应。因为 Corynebacteria在整个身体中都相当无处不在，这些数据将具有深远的影响不仅对眼睛，而且对整个身体的其余部分都有影响。总而言之将构成眼科益生菌未来发展以治疗眼部疾病的基础。