Staphylococcus Biology in Ocular Infections

眼部感染中的葡萄球菌生物学

• 批准号: 10473723
• 负责人: Michelle C Callegan
• 金额: $ 35.16万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473723
• 关键词: Acute; Address; Adherence; Adhesions; Agonist; Animals; Anti-Inflammatory Agents; Antibiotic Resistance; Antibiotics; Area; Attention; Bacteria; Bacterial Adhesins; Bacterial Eye Infections; Bacterial Infections; Binding; Biology; Blindness; Blood-Retinal Barrier; Bypass; Cell Culture Techniques; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Communicable Diseases; Cornea; Data; Development; Disease; Endophthalmitis; Event; Eye; Eye Infections; Future; Genes; Genus staphylococcus; Goals; Growth; Health; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Response; Keratitis; Knowledge; Lead; Mediating; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Organism; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Positioning Attribute; Prevention; Process; Production; Publishing; Regulation; Research; Resistance; Retina; Risk; Speed; Staphylococcus aureus; Strategic Planning; Surface; Testing; Therapeutic; Time; Tissues; Toxin; Virulence; Virulence Factors; Vision; Visual; base; corneal epithelium; design; experimental study; improved; in vivo; ineffective therapies; innate immune pathways; innovation; leukotoxin; methicillin resistant Staphylococcus aureus; mutant; negative affect; preservation; prevent; programs; response; retinal damage; therapeutic development; therapeutic target

PROJECT SUMMARY / ABSTRACT Bacterial eye infections cause a significant number of cases of blindness worldwide. Staphylococcus aureus causes a majority of these infections of the cornea (keratitis) and interior of the eye (endophthal- mitis). S. aureus produces several adhesins on its surface which aid in tissue attachment, surface components which trigger innate immune pathways and inflammation, and toxins which disrupt barriers and kill immune cells. The coordinated synthesis of these virulence factors aids the organism in host survival, and the host is usually negatively affected. In the eye, this can manifest as a painfully damaged cornea or irreversibly damaged retina, resulting in significant vision loss. To make matters worse, S. aureus is considered a Serious Threat on the CDC’s list of Antibiotic Resistance Threats in the US. MRSA and multidrug resistance are now common in ocular isolates, elevating the risk of ocular infections that are difficult to treat. We and others have investigated the pathogenic mechanisms underlying ocular bacterial infections. For S. aureus, animal infection models and ocular cell lines have been used to investigate the areas noted above. We have a very good idea of which toxins damage the cornea and retina and which innate pathways are involved in corneal and intraocular inflammation. This proposal is focused on the factors involved in the earliest events in S. aureus ocular infections, events that, to date, have drawn minimal attention. This new R01 proposal is based on the global hypothesis that coordinated regulation of S. aureus adhesins and toxins facilitate adherence to tissue, barrier breach, and escape from the acute immune response. The scientific premise is based on preliminary and published data demonstrating that: 1) adhesins on the S. aureus surface, when absent, reduce adhesion to corneal cells, 2) leukotoxins, when absent, reduce virulence in keratitis and endophthalmitis, and 3) S. aureus breach of the blood-retina barrier appears to be adhesin- and toxin-mediated. These areas are investigated in three separate but related aims focused on early events in S. aureus keratitis and endophthalmitis. We will use well-characterized S. aureus virulence factor- defective mutants and feasible in vitro and in vivo infection models in rigorous and straightforward experiments designed to define the S. aureus factors important in these events. For patients with eye infections, ineffective treatment often equates with vision loss. Our approaches to addressing these gaps in our field are innovative, translationally relevant, and will move the ocular infectious disease field forward by identifying the S. aureus factors responsible for adhesion to tissue and circumvention of the acute response, possibly uncovering targets that lead to more rational use or development of therapeutics for prevention and treatment of infection. These studies are a logical extension of our ocular infection research program, and we are well positioned to contribute new and important information that will improve options for preventing infection and preserving vision.

项目摘要 /摘要 细菌眼感染引起了全世界的大量失明病例。葡萄球菌 金黄色葡萄球菌引起大多数这些感染角膜（角膜炎）和眼内部的感染 Mitis）。金黄色葡萄球菌在其表面上产生多种粘附剂，有助于组织附着，表面成分 这会引发先天免疫途径和注射，以及破坏障碍并杀死免疫力的毒素 细胞。这些病毒因素的协调合成有助于宿主存活中的生物，宿主是 通常受到负面影响。在眼中，这可能表现为痛苦的角膜或不可逆转的角膜 视网膜受损，导致视力丧失。更糟糕的是，金黄色葡萄球菌被认为是严重的 美国疾病预防控制中心（CDC）抗生素抗性威胁的威胁。 MRSA和多药电阻现在 在眼部分离株中常见，升高了难以治疗的眼部感染的风险。 我们和其他人研究了眼细菌感染的基础病原机制。为了 金黄色葡萄球菌，动物感染模型和眼细胞系已用于研究上述所述区域。 我们有一个很好的主意，哪些毒素会损害角膜和视网膜以及哪些先天途径 参与角膜和眼内炎症。该提案的重点是 金黄色葡萄球菌眼感染的最早事件，迄今为止的事件吸引了最小的关注。 该新的R01提案基于全球假设，即对金黄色葡萄球菌进行了协调监管 粘附素和毒素有助于遵守组织，屏障突破并逃脱急性免疫 回复。科学前提是基于初步和已发布的数据，证明：1）粘合剂 在金黄色葡萄球菌表面，当不存在时，将粘附到角膜细胞上，2）白细胞毒素，当不存在时，还原 角膜炎和内嗜性毒性的毒力，以及3）金黄色葡萄球菌破坏血液 - 逆转障碍似乎是 粘附素和毒素介导的。这些领域是在三个单独的但相关的目的的研究，重点是早期 金黄色葡萄球菌角膜炎和内脑炎的事件。我们将使用良好的金黄色葡萄球菌病毒因子 - 严格且直截了当的实验中有缺陷的突变体和可行的体外和体内感染模型 旨在定义在这些事件中重要的金黄色葡萄球菌因素。 对于眼感染的患者，无效的治疗通常等于视力丧失。我们的方法 解决我们领域的这些差距是创新的，翻译的，并将移动眼部感染力 通过识别负责组织和规避广告的金黄色葡萄球菌因素来向前疾病领域 急性响应，可能会发现导致更多合理使用或发展的目标 预防和治疗感染的治疗剂。这些研究是我们眼的逻辑扩展 感染研究计划，我们有能力贡献新的重要信息 改善预防感染和保持视力的选择。