Role of Staphylococcus aureus alpha-hemolysin in disease

金黄色葡萄球菌α-溶血素在疾病中的作用

基本信息

批准号：
8769143
负责人：
Juliane Bubeck Wardenburg
金额：
$ 39万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8769143
关键词：
ADAM Family Protein Acute suppurative arthritis due to bacteria Anti-Infective Agents Antimicrobial Resistance Bacterial Infections Binding Biological Models Biology Blood Circulation Cells Central Nervous System Infections Cessation of life Complex Cornea Coupled Couples Cytolysis Cytotoxin Disease Disintegrins Drug resistance E-Cadherin Economic Burden Elements Enterotoxins Epidemic Epithelial Epithelial Cells Epithelium Eye Infections Family Focal Adhesions Future Gastrointestinal Diseases Genes Genome Goals Hemolysin Human Infection Injury Intercellular Junctions Investigation Knock-out Knockout Mice Knowledge Laboratories Lactams Life Light Lower respiratory tract structure Lung Maps Mediating Metalloproteases Methicillin Modeling Molecular Morbidity - disease rate Mus Neuraxis Organ Organism Osteomyelitis Pathogenesis Pneumonia Predisposition Property Proteins Resistance Role Sepsis Signal Pathway Signal Transduction Skin Skin Tissue Soft Tissue Infections Species Specificity Staphylococcal Infections Staphylococcus aureus Structure Therapeutic Therapeutic Agents Tissue Microarray Tissues Toxic Shock Syndrome Toxin United States Vaccines Virulence Virulent Widespread Disease Zinc antimicrobial antimicrobial drug base cell injury cytotoxicity injured intercellular communication meetings methicillin resistant Staphylococcus aureus microorganism mouse model novel pathogen prevent protein protein interaction receptor receptor function soft tissue trafficking

项目摘要

DESCRIPTION (provided by applicant): Role of Staphylococcus aureus alpha-hemolysin in disease Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the United States. Demonstrating the broad tissue range and virulence properties of the pathogen, S. aureus also causes osteomyelitis, septic arthritis, and a spectrum of toxin-mediated entities including staphylococcal toxic shock syndrome, enterotoxin-induced gastrointestinal disease, and life-threatening desquamation caused by a family of epidermolytic toxins. Recent estimates suggest that S. aureus contributes to half a million infections per year in the United States alone, resulting in nearly 20,000 deaths. The annual economic burden of S. aureus infection reached $14.5 billion in 2003, a rate of increase per annum of 11.9% when compared to 1998. The remarkable pathogenic potential of S. aureus has been demonstrated over the past 15 years by the rapid spread of highly virulent strains worldwide. Current epidemic strains harbor genes encoding for resistance to methicillin (MRSA), rendering the once highly potent class of 2-lactam antimicrobials obsolete as therapeutic agents. To date, there is no commercially available vaccine to prevent S. aureus infection, and novel antimicrobial agents that successfully target this organism have been few. In the context of widespread disease that has been met with a paucity of highly effective, durable anti-infective strategies, it is imperative that we obtain a more detailed understanding of the molecular mechanisms of S. aureus pathogenesis. S. aureus encodes an array of secreted toxins that contribute to host tissue injury. While many of these toxins are variably expressed in distinct strains, the pore-forming cytotoxin alpha-hemolysin (Hla) is encoded in the genome and expressed by almost all S. aureus strains. Hla is a potent epithelial toxin, contributing to the pathogenesis of pneumonia, skin and corneal infection, central nervous system infection, toxic shock syndrome and sepsis. The primary goal of this application is to develop a refined view of how Hla injures cells and epithelial tissues, leading to disease. This application is based on four fundamental discoveries: 1) Hla is required for the pathogenesis of pneumonia and other staphylococcal infections, and preventative and therapeutic strategies that antagonize toxin action afford protection against disease; 2) Hla binds to ADAM10 as its eukaryotic cellular receptor, thus, cell sensitivity to Hla is conferred by expression of ADAM10; 3) Hla utilizes the native cellular activity of ADAM10 to cause host tissue injury; and 4) ADAM10 is required for Hla- mediated lethal infection in the lung. Through studies that reveal the precise mechanism by which the Hla- ADAM10 complex results in host cell injury, we anticipate the discovery of novel, focused therapies that interfere with the fundamental elements of the host-pathogen interface. These studies are expected to shed light on elements of host susceptibility to S. aureus disease, and contribute more broadly to our understanding of bacterial pore forming cytotoxins.

描述（由申请人提供）：金黄色葡萄球菌在疾病金黄色葡萄球菌中的作用是美国血流，下呼吸道，皮肤和软组织感染的主要原因。在病原体的宽组织范围和毒力特性中，金黄色葡萄球菌还会引起骨髓炎，化脓性关节炎以及毒素介导的实体谱，包括肠毒素肠毒素，肠毒素诱导的胃肠道疾病，胃肠道疾病，抗毒素造成的抗药性剂和势力抗药性。最近的估计表明，仅在美国，金黄色葡萄球菌每年就会贡献50万个感染，导致近20,000人死亡。金黄色葡萄球菌感染的年度经济负担在2003年达到145亿美元，与1998年相比，每年的增长率为11.9％。在过去15年中，由于全球高度毒力的菌株的迅速传播，已证明了金黄色葡萄球菌的显着致病潜力。当前的流行菌株携带编码甲基甲基蛋白（MRSA）的基因，使曾经高度有效的2-乳糖果抗菌抗菌药物过时为治疗剂。迄今为止，还没有可预防金黄色葡萄球菌感染的市售疫苗，并且成功靶向这种生物的新型抗菌剂很少。在广泛的疾病的背景下，这种疾病已经缺乏高效，耐用的抗感染策略，我们必须对金黄色葡萄球菌发病机理的分子机制进行更详细的了解。金黄色葡萄球菌编码有助于宿主组织损伤的一系列分泌毒素。尽管这些毒素中的许多以不同的菌株形式表达，但孔形成的细胞毒素α-溶血素（HLA）在基因组中编码，几乎由所有金黄色葡萄球菌菌株表达。 HLA是一种有效的上皮毒素，导致肺炎，皮肤和角膜感染的发病机理，中枢神经系统感染，毒性休克综合征和败血症。该应用的主要目的是对HLA如何损害细胞和上皮组织，从而形成一种精致的看法，从而导致疾病。该应用基于四个基本发现：1）HLA是肺炎和其他葡萄球菌感染的发病机理所必需的，以及预防性和治疗策略，可以拮抗毒素作用可保护疾病； 2）HLA与ADAM10结合为其真核细胞受体，因此，通过ADAM10的表达赋予细胞对HLA的敏感性； 3）HLA利用ADAM10的天然细胞活性引起宿主组织损伤； 4）ADAM10是肺中HLA介导的致死感染所必需的。通过揭示HLA-ADAM10复合物导致宿主细胞损伤的确切机制的研究，我们预计会发现新颖的，重点的疗法会干扰宿主 - 疾病原子界面的基本元素。预计这些研究将阐明宿主对金黄色葡萄球菌疾病的易感性，并为我们对细菌形成细胞毒素的理解做出更广泛的贡献。