Role of Staphylococcus aureus alpha-hemolysin in disease

描述（由申请人提供）：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液、下呼吸道、皮肤和软组织感染的主要原因。金黄色葡萄球菌具有广泛的组织范围和毒力特性，也可引起骨髓炎、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，以及由表皮松解毒素家族引起的危及生命的脱屑。最近的估计表明，仅在美国，金黄色葡萄球菌每年就造成50万例感染，导致近2万人死亡。2003年，金黄色葡萄球菌感染每年造成的经济负担达145亿元，与1998年相比，每年增长11.9%。金黄色葡萄球菌具有显著的致病潜力，在过去15年中，高毒力菌株在世界范围内的迅速传播证明了这一点。目前流行的菌株含有对甲氧西林（MRSA）耐药的基因，使得曾经非常有效的2-内酰胺类抗菌剂作为治疗药物已经过时。迄今为止，市面上还没有预防金黄色葡萄球菌感染的疫苗，而成功靶向这种生物的新型抗菌药物也很少。在广泛传播疾病的背景下，缺乏高效、持久的抗感染策略，我们必须更详细地了解金黄色葡萄球菌发病机制的分子机制。金黄色葡萄球菌编码一系列导致宿主组织损伤的分泌毒素。虽然这些毒素中的许多在不同菌株中表达不同，但形成孔的细胞毒素α -溶血素（Hla）在基因组中编码，并在几乎所有金黄色葡萄球菌菌株中表达。Hla是一种有效的上皮毒素，参与肺炎、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的发病机制。该应用程序的主要目标是开发Hla如何损伤细胞和上皮组织，导致疾病的精细视图。这一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制所必需的，拮抗毒素作用的预防和治疗策略提供了对疾病的保护；2) Hla作为真核细胞受体与ADAM10结合，因此细胞对Hla的敏感性通过ADAM10的表达获得；3) Hla利用ADAM10的天然细胞活性引起宿主组织损伤；4)在Hla介导的肺致死性感染中ADAM10是必需的。通过揭示Hla- ADAM10复合物导致宿主细胞损伤的精确机制的研究，我们预计会发现干扰宿主-病原体界面基本元素的新颖、集中的治疗方法。这些研究有望揭示宿主对金黄色葡萄球菌病易感性的因素，并更广泛地促进我们对细菌孔形成细胞毒素的理解。公共卫生相关性：在美国，金黄色葡萄球菌是导致血液、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；其中许多现在是由耐药金黄色葡萄球菌引起的，这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。

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.