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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：
10414042
负责人：
ANTHONY J ST LEGER
金额：
$ 38.51万
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/10414042
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 Glaucoma Goals Health Hour Human Immune Immune response Immunity In Vitro Infection Inflammation Interleukin-1 beta Interleukin-17 Knowledge Laboratories Libraries Ligation Light 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 Sum Symbiosis T-Cell Receptor Testing Time Translating Universities Visual impairment antimicrobial clinically relevant commensal bacteria cost host-microbe interactions immunogenicity in vivo insight microbial microbiome mutant novel novel therapeutics ocular microbiome ocular surface 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给人类带来超过 120 亿美元的惊人经济负担治疗。虽然当前的护理标准仅治疗症状而不是解决原因疾病，最近的数据表明，操纵微生物组可能是一个潜在的途径治疗和/或预防疾病。最近，一种眼部共生细菌——棒状杆菌乳腺炎 (C. mast) 已被鉴定并显示可以保护眼表面免受乳腺炎乳腺炎 (C. mast) 感染。白色念珠菌和铜绿假单胞菌。尽管有这种有益的免疫力，但仍然需要了解控制眼部定植和刺激宿主免疫能力的微生物因素回复。拟议研究的基础是建立在从以下机构获得的初步数据之上的：对 30 多个临床相关的棒状杆菌分离株进行基因组和表型筛选种。以及近2000个C. mast转座子突变体。具体来说，第一个目标将确定通过测试八个 C. mast 突变体来控制眼部定植的微生物因子预计缺乏定植于眼睛的能力。第二个目标是发现微生物因素通过评估九种不同的 C. 体外和体内免疫原性来刺激宿主免疫力。预计诱导免疫反应能力有限的肥大突变体。第三个目标将机械地定义眼部共生细菌如何刺激人体免疫回复。如上所述，拟议的研究将提供有益的多层信息为了眼睛健康。首先，目标 1 和 2 将提供发挥关键作用的特定基因的身份。在眼共生本质中的作用，这将使未来的研究能够更好地区分真实的来自暂时引入眼睛的其他细菌的眼共生体。这些目标还将揭示在转基因眼药配方中可能需要的基因细菌或眼部益生菌。最后，Aim 3 将提供有关几乎未知的宝贵知识区域，这是人体针对棒状杆菌属的免疫反应。因为棒状杆菌在人体中相当普遍，这些数据将产生深远的影响不仅对眼睛有影响，而且对身体的其他部位也有影响。总之，拟议的研究将为未来开发眼部益生菌治疗眼部疾病奠定基础。