ESAT-6 Secretion in Staphylococcus Aureus

描述(由申请人提供)：由金黄色葡萄球菌引起的人类感染是一个严重的治疗挑战，因为出现了抗药性菌株。最令人担忧的是感染耐甲氧西林金黄色葡萄球菌(MRSA)、高毒力微生物和美国医院最常见的传染病。耐甲氧西林金黄色葡萄球菌已经获得了对所有已知抗生素的耐药性机制，许多分离株对大多数抗感染药物具有广泛的耐药性。未来的研究必须着眼于了解MRSA发病机制的分子生物学，以及开发预防MRSA传染病的特定疫苗。这一建议揭示了金黄色葡萄球菌的一种特殊分泌系统，它参与了人和动物感染的发病机制。金黄色葡萄球菌ess(ESAT-6分泌系统)基因座由8个基因组成，其中3个基因(esxA、esxB和esac)编码需要机械基因essABC的机制分泌的产物。在感染过程中，小鼠和人类宿主都对EsxA、EsxB和EsC产生体液免疫反应，这表明所有临床分离的金黄色葡萄球菌在体内都参与了Ess的分泌。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疾病。Ess途径是葡萄球菌感染发病机制所必需的，因为esxB突变株无法在宿主组织中形成脓肿或持续存在，而影响ESAC分泌的突变株最初复制，但随后未能持续存在。首先感染野生型金黄色葡萄球菌的动物仍然对随后的金黄色葡萄球菌感染敏感，而感染esxB突变的动物对随后的金黄色葡萄球菌感染产生免疫力。在这里，我们将探索金黄色葡萄球菌的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突变体被询问产生对金黄色葡萄球菌疾病保护性免疫的遗传要求。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，每年的发病率约为300万，每年的死亡率接近10万美国人。我们对慢性持续性感染的发展以及ESAT-6分泌系统在阻止金黄色葡萄球菌保护性免疫发展中的作用进行了研究，旨在揭示其发病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.