ESAT-6 Secretion in Staphylococcus Aureus

金黄色葡萄球菌中的 ESAT-6 分泌

• 批准号: 7742680
• 负责人: Dominique M. Missiakas
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-05 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742680
• 关键词: Abscess; American; Amino Acid Sequence; Animals; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Antigens; Biochemical; Blood; Blood Circulation; Chronic; Clinical; Communicable Diseases; Development; Disease; Future; Genes; Genetic; Growth; Hospitals; Human; Immune response; Immunity; Immunization; Infection; Life; Lower respiratory tract structure; Maps; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Organ; Pathogenesis; Pathway interactions; Proteins; Research; Resistance; Role; Rupture; Site; Skin; Soft Tissue Infections; Staphylococcal Infections; Staphylococcus aureus; System; Therapeutic; Tissues; Ubiquitin; United States; Vaccines; Variant; Virulence; Virulent; base; design; in vivo; methicillin resistant Staphylococcus aureus; microorganism; mortality; mutant; pathogen; polypeptide; prevent; public health relevance; resistance mechanism; resistant strain

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.

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提出了严峻的治疗挑战。最令人担忧的是耐甲氧西林金黄色葡萄球菌（MRSA）感染，这是一种高毒力微生物，也是美国医院中最常见的传染病。 MRSA 已获得对所有已知抗生素的耐药机制，并且许多分离株对大多数抗感染药物具有广泛耐药性。未来的研究必须旨在了解 MRSA 发病机制的分子生物学，并开发预防 MRSA 传染病的特定疫苗。该提议揭示了金黄色葡萄球菌的特殊分泌系统，该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）基因座由八个基因组成，其中三个（esxA、esxB 和 esaC）编码由需要机械基因 essABC 的机制分泌的产物。在感染过程中，小鼠和人类宿主都会产生针对 EsxA、EsxB 和 EsaC 的体液免疫反应，这表明所有临床金黄色葡萄球菌分离株都会在体内参与 Ess 分泌。我们发现金黄色葡萄球菌会导致实验动物持续感染，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 突变体无法形成脓肿或在宿主组织中持续存在，而影响 EsaC 分泌的突变体最初会复制，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仍然容易受到随后的葡萄球菌感染，而感染 esxB 突变体的动物则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，还研究了葡萄球菌 esxB 突变体产生针对金黄色葡萄球菌疾病的保护性免疫力的遗传要求。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，每年约有 300 万人发病，每年约有 10 万人死亡。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贡献的研究旨在揭示发病机制的分子基础以及保护性免疫的目标。