Mechanisms underlying adhesion and colonization in pneumococcal keratitis

肺炎球菌角膜炎粘附和定植的机制

• 批准号: 10727764
• 负责人: Brian Akerley
• 金额: $ 42.63万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727764
• 关键词: Adhesions; Anabolism; Antibiotic Resistance; Antibiotics; Automobile Driving; Bacteria; Bacterial Adhesins; Bacterial Attachment Site; Bacterial Capsules; Blindness; Cells; Cellular Assay; Clinical; Complement; Cornea; Data; Development; Disease; Epithelial Cells; Exercise; Eye; Eye Infections; Future; Gene Deletion; Genes; Genetic; Genetic Screening; Goals; Human; Immune system; In Vitro; Infection; Keratitis; Knowledge; Libraries; Mediating; Methods; Modeling; Mus; Mutation; Organism; Pathogenesis; Pneumococcal vaccine; Pneumonia; Polysaccharides; Predisposition; Process; Production; Regulation; Repression; Research; Resolution; Septicemia; Streptococcus pneumoniae; Surface; Testing; Validation; Virulence Factors; Vision; Visual impairment; Work; capsule; corneal epithelium; gene product; genomic locus; in vivo; mouse model; mutant; novel therapeutic intervention; novel therapeutics; ocular surface; preservation

Project Summary/Abstract Streptococcus pneumoniae is one of the top bacterial causes of keratitis worldwide and can lead to significant vision loss. The mainstay of therapy continues to be antibiotics; however, bacteria are not always susceptible, and antibiotics are unable to reduce the host- and bacterium-mediated damage associated with S. pneumoniae keratitis. Our findings strongly indicate that the outer polysaccharide capsule of S. pneumoniae, considered a major virulence factor of this organism, impedes attachment of the bacteria to the corneal surface. Preliminary data show that the bacteria produce markedly less capsule when adhered to corneal epithelial cells, which suggest that they regulate capsule to adapt to the corneal niche. Therefore, our central hypothesis is that S. pneumoniae adapts to down-regulate capsule in the present of corneal cells so that attachment and persistence are increased. We will test our hypothesis by comparing capsule quantities of bacteria that are adherent to corneal cells and the corneal surface to bacteria that are not adherent. We will then determine the genes that are necessary for corneal attachment and colonization by a prioritized genetic screen of a library of mutants in vitro and in vivo, followed by validation with functional analyses with targeted mutations. The long- term goals of this study are to identify and characterize the factors that repress bacterial capsule in the cornea and promote attachment to cause keratitis. Understanding the processes of regulation and colonization will aid in driving development of novel therapies to preserve the cornea.

项目总结/文摘