Staphylococcus Biology in Ocular Infections

眼部感染中的葡萄球菌生物学

基本信息

批准号：
10672933
负责人：
Michelle C Callegan
金额：
$ 36.25万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
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：
2021-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672933
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 Communicable Diseases Cornea Data Development Disease Endophthalmitis Equation Event Experimental Designs 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 Invaded Keratitis Knowledge 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 corneal epithelium design 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

项目摘要

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.

项目概要/摘要细菌性眼部感染导致全球大量葡萄球菌失明。金黄色葡萄球菌引起的大部分角膜感染（角膜炎）和眼内感染（眼内感染）金黄色葡萄球菌在其表面产生多种粘附素，有助于组织附着、表面成分。触发先天免疫途径和炎症，以及破坏屏障和杀死免疫的毒素这些毒力因子的协调合成有助于宿主生存，而宿主是通常会对眼睛造成负面影响，表现为角膜损伤或不可逆转。视网膜受损，导致视力严重丧失，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) 的抗生素耐药性威胁清单中的威胁现已列入 MRSA 和多重耐药性。常见于眼部分离株，增加了难以治疗的眼部感染的风险。我们和其他人研究了眼部细菌感染的致病机制。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领域。我们非常清楚哪些毒素会损害角膜和视网膜，以及哪些先天途径会损害角膜和视网膜。该提案的重点是涉及角膜和眼内炎症的因素。金黄色葡萄球菌眼部感染的最早事件，迄今为止，这些事件引起的关注很少。这项新的 R01 提案基于金黄色葡萄球菌协调调节的全球假设粘附素和毒素有助于粘附组织、突破屏障和逃避急性免疫科学前提基于初步和已发表的数据，表明：1) 粘附素。在金黄色葡萄球菌表面，当不存在时，减少对角膜细胞的粘附，2) 白细胞毒素，当不存在时，减少角膜炎和眼内炎的毒力，以及 3) 金黄色葡萄球菌突破血-视网膜屏障似乎是这些领域通过三个独立但相关的目标进行研究，重点关注早期。我们将使用已充分表征的金黄色葡萄球菌毒力因子- 在严格和简单的实验中建立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。对于眼部感染患者，无效的治疗通常等同于视力丧失。解决我们领域的这些差距是创新的、具有转化意义的，并将推动眼部传染病的发展通过识别负责组织粘附和规避的金黄色葡萄球菌因子，向前疾病领域迈进的急性反应，可能会发现导致更合理使用或开发的目标这些研究是我们眼科疾病预防和治疗的合理延伸。感染研究计划，我们有能力提供新的重要信息，这些信息将改善预防感染和保护视力的选择。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Role of C-X-C Chemokines in Staphylococcus aureus Endophthalmitis.

C-X-C 趋化因子在金黄色葡萄球菌眼内炎中的作用。

DOI：
发表时间：
2023-03-01
期刊：
影响因子：
4.4
作者：
Coburn, Phillip S;Parrott, Aaron C;Miller, Frederick C;LaGrow, Austin L;Mursalin, Md Huzzatul;Callegan, Michelle C
通讯作者：
Callegan, Michelle C

Ocular Bacterial Infections: A Ten-Year Survey and Review of Causative Organisms Based on the Oklahoma Experience.

眼部细菌感染：基于俄克拉荷马州经验的致病微生物十年调查和回顾。

DOI：
发表时间：
2023-07-13
期刊：
影响因子：
4.5
作者：
Astley, Roger A;Mursalin, Md Huzzatul;Coburn, Phillip S;Livingston, Erin T;Nightengale, James W;Bagaruka, Eddy;Hunt, Jonathan J;Callegan, Michelle C
通讯作者：
Callegan, Michelle C