Role of Staphylococcus aureus alpha-hemolysin in disease

描述(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。金黄色葡萄球菌的广泛组织范围和毒力特性表明，它还会引起骨髓炎、感染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、肠毒素引起的胃肠道疾病以及由一类表皮松解性毒素引起的危及生命的脱皮。最近的估计表明，仅在美国，金黄色葡萄球菌每年就造成50万人感染，导致近2万人死亡。2003年，金黄色葡萄球菌感染造成的年经济负担达145亿美元，与1998年相比，每年增长11.9%。在过去的15年里，金黄色葡萄球菌在世界范围内的高毒力菌株的迅速传播证明了其显著的致病潜力。目前流行的菌株含有对甲氧西林(MRSA)耐药的编码基因，使得曾经高度有效的2-内酰胺类抗菌药作为治疗剂被淘汰。到目前为止，还没有商业上可用的疫苗来预防金黄色葡萄球菌感染，成功针对这种微生物的新型抗菌剂也很少。在普遍存在的疾病缺乏高效、持久的抗感染策略的背景下，我们迫切需要更详细地了解金黄色葡萄球菌致病的分子机制。金黄色葡萄球菌编码一系列分泌的毒素，这些毒素会导致宿主组织损伤。虽然这些毒素中的许多在不同的菌株中有不同的表达，但形成孔洞的细胞毒素α-溶血素(Hla)在基因组中编码并在几乎所有的金黄色葡萄球菌菌株中表达。人类白细胞抗原是一种强效的上皮性毒素，可引起肺炎、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。这项应用的主要目标是对人类白细胞抗原如何损伤细胞和上皮组织，从而导致疾病，形成一个精细的观点。这一应用是基于四个基本发现：1)肺炎和其他葡萄球菌感染的发病需要人类白细胞抗原，拮抗毒素作用的预防和治疗策略提供了对疾病的保护；2)人类白细胞抗原作为其真核细胞受体与ADAM10结合，因此，细胞对人类白细胞抗原的敏感性是通过表达ADAM10来实现的；3)人类白细胞抗原利用ADAM10的天然细胞活性来引起宿主组织损伤；以及4)人类白细胞抗原10是人类白细胞抗原介导的肺部致死性感染所必需的。通过研究揭示人类白细胞抗原-ADAM10复合体导致宿主细胞损伤的确切机制，我们预计会发现干扰宿主-病原体界面基本成分的新型、重点治疗方法。这些研究有望阐明宿主对金黄色葡萄球菌病的易感因素，并有助于我们更广泛地了解细菌形成毛孔的细胞毒素。

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.