ESAT-6 Secretion in Staphylococcus Aureus

由金黄色葡萄球菌引起的人类感染呈现严重的治疗方法 由于抗生素耐药菌株的出现而带来的挑战。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 也是美国医院最常见的传染病。MRSA已经获得了 对所有已知抗生素和许多分离株的耐药性机制都是广泛耐药的 对抗大多数抗感染药物。未来的研究必须着眼于理解 耐甲氧西林金黄色葡萄球菌致病机理的分子生物学和特异性疫苗的开发 预防耐甲氧西林金黄色葡萄球菌传染病。这项提议揭示了一种特殊的分泌物 金黄色葡萄球菌系统，参与人类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， 其中三个(esxA、esxB和esac)编码由 机制需要机械基因essABC。在感染期间，无论是小鼠还是 人类宿主对EsxA、EsxB和ESAC产生体液免疫反应，提示 所有临床分离的金黄色葡萄球菌在体内都能分泌Ess。我们证明了金黄色葡萄球菌 在实验动物中引起持续性感染，类似于葡萄球菌病 人类。Ess途径是葡萄球菌感染致病所必需的， 因为esxB突变体不能在宿主组织中形成脓肿或持续存在，而 影响ESAC分泌的突变体最初会复制，但随后无法持续。动物 首次感染野生型金黄色葡萄球菌后仍易感染葡萄球菌 感染，而感染esxB突变体的动物对随后的 金黄色葡萄球菌感染。在这里，我们将探索金黄色葡萄球菌的Ess途径，以揭开 脓肿形成和持续性感染的分子基础。此外， 葡萄球菌esxB突变体被询问产生的遗传要求 对金黄色葡萄球菌病的保护性免疫。

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.