Virulence mechanisms of group A streptococcal toxins

A组链球菌毒素的毒力机制

• 批准号: 7849522
• 负责人: MICHAEL R WESSELS
• 金额: $ 38.24万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849522
• 关键词: Accounting; Antibiotic Therapy; Area; Autophagocytosis; Bacteria; Binding; Biological Models; Cell Culture Techniques; Cell Line; Cells; Cellular biology; Cessation of life; Complication; Confocal Microscopy; Data; Developing Countries; Development; Dose; Economics; Employee Strikes; Enzymes; Epithelial Cells; Epithelium; Evolution; Exocytosis; Goals; Grant; Hand; Heart Diseases; Hexosaminidases; Host Defense Mechanism; Human; Human Cell Line; Imaging Techniques; In Vitro; Infection; Infectious Skin Diseases; Integrins; Investigation; Laboratories; Lead; Life; Location; Lysosomes; Mediating; Membrane Microdomains; Modeling; Molecular; Morbidity - disease rate; NAD+ Nucleosidase; Nature; Oropharyngeal; Outcome; Pathogenesis; Pharyngeal structure; Pharyngitis; Plasmids; Preparation; Prevention; Prevention approach; Process; Published Comment; Publishing; Reagent; Refractory; Relapse; Research; Research Personnel; Rheumatic Fever; Rheumatic Heart Disease; Role; Series; Sore Throat; Streptococcal Infections; Streptococcus pyogenes; Surface; System; Techniques; Testing; Toxin; Treatment Failure; United States; Vaccines; Virulence; Work; base; beta-n-acetylhexosaminidase; capsule; cellular imaging; immortalized cell; in vitro Assay; insight; keratinocyte; killings; mutant; novel; novel strategies; pathogen; prevent; research study; response; soft tissue; streptolysin O; tool

DESCRIPTION (provided by applicant): Streptococcus pyogenes or group A Streptococcus (GAS) is the agent of streptococcal pharyngitis, infections of the skin and soft tissue, and life-threatening invasive infections. GAS infections and post-infectious sequelae, primarily in the form of rheumatic heart disease, account for 500,000 deaths annually in addition to morbidity and economic losses. A vaccine is not yet available and antibiotic treatment fails or is followed by relapse in 10 to 20 percent of pharyngitis cases. The refractory nature of GAS infection may reflect the co-evolution of GAS with human beings and its exquisite adaptation for survival in the human pharynx, its primary environmental niche. We and others have observed entry of GAS into human epithelial cells in vitro. While intracellular bacteria are eventually killed, we have found that GAS co-toxins streptolysin O and NADase inhibit GAS internalization and prolong intracellular survival, effects that may contribute to antibiotic treatment failure, relapse, and prolonged carriage. The goal of this proposal is to determine how SLO and NADase block internalization of GAS by pharyngeal epithelial cells and prevent effective intracellular killing. Specific aims are (1) to characterize internalization of GAS by pharyngeal epithelial cells, (2) to determine the specific roles of SLO and NADase in blocking internalization, and (3) to define the molecular mechanisms by which GAS avoids or escapes intracellular killing. In preliminary studies, we have found striking effects of SLO and NADase on the fate of GAS during interaction with keratinocytes. We have assembled the necessary molecular tools, cell culture models, and imaging techniques to decipher how these toxins and host cellular mechanisms determine the outcome of this critical pathogen-host interaction at the pharyngeal epithelium. The results will inform new approaches to prevention and treatment of GAS infection. Project Narrative: Group A Streptococcus or GAS is responsible for millions of cases of streptococcal sore throat and approximately 10,000 cases of life-threatening invasive infections annually in the United States, and rheumatic fever, a complication of GAS infection, is a leading cause of often fatal heart disease in developing countries. The objective of this project is determine how cells lining the human throat ingest and kill GAS, thereby blocking GAS infection, and how two GAS toxins act to counteract this host defense mechanism. Understanding these interactions may lead to novel strategies for prevention or treatment of GAS infections.

描述(申请人提供)：化脓性链球菌或A组链球菌(GAS)是链球菌性咽炎、皮肤和软组织感染以及危及生命的侵袭性感染的病原体。除发病率和经济损失外，气体感染和感染后后遗症，主要以风湿性心脏病的形式，每年造成50万人死亡。目前还没有疫苗，在10%到20%的咽炎病例中，抗生素治疗失败或复发。气体感染的难治性可能反映了气体与人类的共同进化，以及它对人类咽部生存的精致适应，人类咽部是它的主要环境生态位。我们和其他人在体外观察到GAS进入人体上皮细胞。虽然细胞内的细菌最终会被杀死，但我们已经发现，气体联合毒素链球菌溶血素O和NADase抑制气体内化，延长细胞内存活，这可能导致抗生素治疗失败、复发和长时间携带。这项建议的目的是确定SLO和NADase如何阻止咽上皮细胞内化GAS，并防止有效的细胞内杀伤。其具体目标是(1)确定咽上皮细胞对GAS的内化作用，(2)确定SLO和NADase在阻断内化中的特定作用，以及(3)确定GAS避免或逃避细胞内杀伤的分子机制。在初步研究中，我们发现SLO和NADase在与角质形成细胞相互作用过程中对GAS的命运有显著的影响。我们已经组装了必要的分子工具、细胞培养模型和成像技术，以破译这些毒素和宿主细胞机制如何决定咽上皮这一关键病原体-宿主相互作用的结果。这一结果将为预防和治疗气体感染提供新的方法。 项目简介：A组链球菌或GAS每年在美国导致数百万例链球菌喉咙痛和约10,000例危及生命的侵入性感染，风湿热是GAS感染的并发症，是发展中国家往往致命的心脏病的主要原因。这个项目的目标是确定人体喉咙内的细胞如何摄取和杀死气体，从而阻止气体感染，以及两种气体毒素如何作用于抵消这种宿主防御机制。了解这些相互作用可能会导致预防或治疗气体感染的新策略。