Role of Staphylococcus aureus alpha-hemolysin in disease

描述（由申请方提供）：金黄色葡萄球菌α-溶血素在疾病中的作用金黄色葡萄球菌是美国血流、下呼吸道、皮肤和软组织感染的主要原因。证明了病原体的广泛组织范围和毒力特性，S。金黄色葡萄球菌还引起骨髓炎、脓毒性关节炎和一系列毒素介导的实体，包括葡萄球菌中毒性休克综合征、肠毒素诱导的胃肠道疾病和由表皮毒素家族引起的危及生命的脱屑。最近的估计表明，S。仅在美国，金黄色葡萄球菌每年就导致50万例感染，导致近20，000人死亡。S.在二〇 〇三年，金葡菌感染的开支达145亿元，与一九九八年比较，每年的增幅为11.9%。S.在过去的15年中，高毒性菌株在全世界的快速传播已经证明了金黄色葡萄球菌。目前流行的菌株携带编码甲氧西林（MRSA）抗性的基因，使得曾经非常有效的2-内酰胺类抗菌剂作为治疗剂过时。到目前为止，还没有商业上可用的疫苗来预防S。金黄色葡萄球菌感染，并且成功靶向该生物体的新型抗微生物剂很少。在广泛传播的疾病的背景下，已经遇到了缺乏高效，持久的抗感染策略，我们必须获得更详细的了解的分子机制的S。金黄色葡萄球菌发病机制S.金黄色葡萄球菌编码一系列有助于宿主组织损伤的分泌毒素。虽然这些毒素中的许多在不同的菌株中不稳定表达，但成孔细胞毒素α-溶血素（Hla）在基因组中编码并由几乎所有的S.金黄色葡萄球菌Hla是一种强效上皮毒素，可导致肺炎、皮肤和角膜感染、中枢神经系统感染、中毒性休克综合征和败血症。该应用的主要目标是开发Hla如何损伤细胞和上皮组织从而导致疾病的精细视图。本申请基于四个基本发现：1）Hla是肺炎和其它葡萄球菌感染的发病机理所需的，并且拮抗毒素作用的预防和治疗策略提供针对疾病的保护; 2）Hla结合到作为其真核细胞受体的ADAM 10，因此，细胞对Hla的敏感性是通过ADAM 10的表达而赋予的; 3）Hla利用ADAM 10的天然细胞活性引起宿主组织损伤;和4）ADAM 10是肺中Hla介导的致死性感染所需的。通过揭示Hla-ADAM 10复合物导致宿主细胞损伤的精确机制的研究，我们预期发现干扰宿主-病原体界面的基本要素的新颖的、集中的疗法。这些研究有望揭示寄主对S.金黄色葡萄球菌病，并有助于更广泛地了解细菌孔形成细胞毒素。公共卫生相关性：金黄色葡萄球菌是美国血液、下呼吸道、皮肤和软组织感染的主要原因。仅在美国，每年就有近50万例感染病例，其中许多是由耐药的沙门氏菌引起的。金黄色葡萄球菌，对目前治疗这些感染和开发未来可能应用的有效预防和治疗提出了挑战。 公共卫生相关性：金黄色葡萄球菌是一种侵袭性的人类病原体，仅在美国每年就造成约500，000例感染，导致近20，000人死亡。高度耐药菌株已在世界各地蔓延，要求开发新的策略来预防和治疗感染。这些策略的设计需要我们清楚地了解S。金黄色葡萄球菌在发病过程中损伤其宿主，这是本申请的焦点。

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. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the United States. Nearly half a million cases of infection occur per year in the US alone; many of these are now caused by drug-resistant S. aureus, posing a challenge to both treat these infections at present, and develop effective preventatives and therapies that may be applied in the future. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus is an aggressive human pathogen, contributing to an estimated 500,000 infections that claim the life of nearly 20,000 individuals per year in the US alone. Highly drug resistant strains have spread throughout the world, mandating the development of novel strategies to prevent and treat infection. The design of such strategies necessitates that we obtain a clear understanding of the mechanisms by which S. aureus injures its host during pathogenesis, which is the focus of this application.