ESAT-6 Secretion in Staphylococcus Aureus

描述（由申请方提供）：由于出现了耐药菌株，金黄色葡萄球菌引起的人类感染给治疗带来了严重挑战。主要关注的是耐甲氧西林沙门氏菌的感染。金黄色葡萄球菌（MRSA），高毒力微生物和美国医院最常见的传染病。MRSA对所有已知的抗生素具有获得性耐药机制，并且许多分离株对大多数抗感染剂具有广泛耐药性。未来的研究必须致力于了解MRSA发病机制的分子生物学和预防MRSA感染性疾病的特异性疫苗的开发。这一建议揭示了一个专门的分泌系统的S。金黄色葡萄球菌，其参与人类和动物感染的发病机制。色葡萄金黄色葡萄球菌ess（ESAT-6分泌系统）基因座由8个基因的簇组成，其中3个（esxA、esxB和esaC）编码通过需要机械基因essABC的机制分泌的产物。在感染过程中，鼠和人宿主均产生对EsxA、EsxB和EsaC的体液免疫应答，这表明所有临床S.金黄色葡萄球菌分离株在体内参与Ess分泌。我们证明了S.金黄色葡萄球菌引起实验动物的持续感染，类似于人类的葡萄球菌病。葡萄球菌感染的发病机制需要Ess途径，因为esxB突变体不能在宿主组织中形成复制或持续存在，而影响EsaC分泌的突变体最初复制，但随后不能持续存在。首次感染野生型S.金黄色葡萄球菌仍然对随后的葡萄球菌感染敏感，而感染esxB突变体的动物对随后的S.金黄色葡萄球菌感染在这里，我们将探讨S的Ess途径。金黄色葡萄球菌，以解开脓肿形成和持续感染的分子基础。此外，葡萄球菌esxB突变体被询问产生针对S的保护性免疫的遗传要求。金黄色葡萄球菌病公共卫生相关性：金黄色葡萄球菌（Staphylococcus aureus）是美国血流、下呼吸道、皮肤和软组织感染的主要原因，年发病率约为300万，年死亡率接近10万美国人。我们对慢性持续性感染的发展以及ESAT-6分泌系统在阻止针对S.金黄色葡萄球菌的目的是揭示发病机制的分子基础以及保护性免疫的靶点。

DESCRIPTION (provided by applicant): Human infections caused by Staphylococcus aureus present a serious therapeutic challenge due to the emergence of antibiotic-resistant strains. Of major concern are infections with methicillin-resistant S. aureus (MRSA), highly virulent microorganisms and the most common infectious disease in American hospitals. MRSA have acquired resistance mechanisms to all known antibiotics and many isolates are broadly resistant against most antiinfective agents. Future research must aim at understanding the molecular biology of MRSA pathogenesis and the development of specific vaccines that prevent MRSA infectious diseases. This proposal reveals a specialized secretion system of S. aureus that is involved in the pathogenesis of human and animal infections. The S. aureus ess (ESAT-6 secretion system) locus consists of a cluster of eight genes, three of which (esxA, esxB and esaC) encode products that are secreted by a mechanism requiring the machinery genes essABC. During infection, both murine and human hosts generate humoral immune responses to EsxA, EsxB and EsaC, suggesting that all clinical S. aureus isolates engage Ess secretion in vivo. We show that S. aureus causes persistent infections in experimental animals, similar to staphylococcal disease in humans. The Ess pathway is required for the pathogenesis of staphylococcal infections, as esxB mutants are unable to form abscesses or persist in host tissues, whereas mutants that impact EsaC secretion initially replicate but then fail to persist. Animals first infected with wild-type S. aureus remain susceptible to subsequent staphylococcal infection, whereas animals infected with esxB mutants develop immunity to subsequent S. aureus infections. Here we will explore the Ess pathway of S. aureus to unravel the molecular basis of abscess formation and persistent infections. Moreover, staphylococcal esxB mutants are interrogated for the genetic requirements of generating protective immunity against S. aureus disease. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the United States with annual morbidity of about 3 million and annual mortality approaching 100,000 Americans lives. Our research into the development of chronic-persistent infections and the contribution of the ESAT-6 secretion system in preventing the development of protective immunity against S. aureus are designed to reveal the molecular basis of pathogenesis as well as the targets of protective immunity.