ESAT-6 Secretion in Staphylococcus Aureus

描述（由申请人提供）：由于抗生素耐药菌株的出现，由金黄色葡萄球菌引起的人类感染对治疗提出了严重的挑战。主要关注的是耐甲氧西林金黄色葡萄球菌（MRSA）感染，高毒力微生物和美国医院最常见的传染病。MRSA已获得对所有已知抗生素的耐药机制，许多分离株对大多数抗感染药物具有广泛耐药性。未来的研究必须以了解MRSA发病机制的分子生物学和开发预防MRSA传染病的特异性疫苗为目标。这一建议揭示了金黄色葡萄球菌的一个特殊的分泌系统，它参与了人类和动物感染的发病机制。金黄色葡萄球菌（ESAT-6分泌系统）基因座由8个基因簇组成，其中3个基因（esxA、esxB和esaC）编码的产物通过需要机械基因essABC的机制分泌。在感染过程中，小鼠和人类宿主都会对EsxA、EsxB和EsaC产生体液免疫反应，这表明所有临床金黄色葡萄球菌分离株都在体内分泌Ess。我们发现金黄色葡萄球菌在实验动物中引起持续感染，类似于人类的葡萄球菌病。Ess途径是葡萄球菌感染的发病机制所必需的，因为esxB突变体不能形成脓肿或在宿主组织中持续存在，而影响EsaC分泌的突变体最初进行复制，但随后无法持续存在。首先感染野生型金黄色葡萄球菌的动物对随后的葡萄球菌感染仍然敏感，而感染esxB突变体的动物对随后的金黄色葡萄球菌感染产生免疫力。在这里，我们将探讨金黄色葡萄球菌的Ess途径，以揭示脓肿形成和持续感染的分子基础。此外，葡萄球菌esxB突变体被问及产生针对金黄色葡萄球菌疾病的保护性免疫的遗传要求。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，年发病率约为300万，年死亡率接近10万。我们对慢性持续性感染的发展和ESAT-6分泌系统在预防金黄色葡萄球菌保护性免疫发展中的作用的研究旨在揭示其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.