Tissue-Specific Infection by Group A Streptococci

A 组链球菌引起的组织特异性感染

• 批准号: 6846636
• 负责人: Debra E BESSEN
• 金额: $ 29.17万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846636
• 关键词: SCID mouse; Streptococcus pyogenes; bacteria infection mechanism; bacterial disease; bacterial genetics; bacterial proteins; cell cycle; clinical research; cysteine endopeptidases; disease /disorder model; gene expression; gene targeting; host organism interaction; human subject; laboratory rabbit; microarray technology; oral pharyngeal; plasminogen activator; population genetics; protein protein interaction; site directed mutagenesis; skin infection; streptokinase; transcription factor; virulence

DESCRIPTION (provided by applicant): Group A streptococci (GAS) are among the most prevalent of bacterial pathogens, infecting only humans. A hallmark feature of GAS is its molecular and biological diversity among strains. Although GAS can give rise to serious illness, such as autoimmune sequelae and severe invasive disease, most often it causes only a mild infection at superficial sites - the oropharynx (strep throat) or epidermis (impetigo). The throat and skin are the primary tissue reservoirs for GAS, whereby the organism is most successful in reproductive growth and transmission to new hosts. Based on decades of field work, it has become widely recognized that many strains differ in their tissue site preference, giving rise to the concept of distinct throat and skin strains. This recognition strongly suggests that there is an underlying genetic organization that imparts a higher biological order to the diverse strains of this species. A long-term goal is to determine the molecular basis for throat and skin tropisms among GAS. In Preliminary Findings, a diverse set of throat and skin strains were analyzed for linkage disequilibrium between different combinations of loci/alleles, leading to the identification of genes which are likely to be critical for tissue-specific adaptations. The Specific Aims of this proposal are to test the role of the tissue-specific virulence factor candidates in an in vivo mouse model that closely mimics superficial skin infection in humans. Isogenic mutants, and chimeric GAS constructs having a throat gene on a skin strain background, will be constructed and compared for virulence. GAS products to be tested for tissue-specific functions include streptokinase (a plasminogen activator), plasminogen-binding M protein (PAM), the cysteine proteinase SpeB, and transcriptional regulators of GAS virulence gene expression (RofA/Nra and Mga). A better understanding of the molecular basis for throat- and skin-specific infection might aid in the development of vaccines which target essential adaptive traits and thereby, break the chain of transmission.

描述（由申请人提供）：A 族链球菌 (GAS) 是最常见的细菌病原体之一，仅感染人类。 GAS 的一个显着特征是其菌株之间的分子和生物多样性。虽然 GAS 可以引起严重的疾病，例如自身免疫性后遗症和严重的侵袭性疾病，但大多数情况下它只会引起浅表部位的轻度感染 - 口咽（链球菌性咽喉炎）或表皮（脓疱疮）。喉咙和皮肤是 GAS 的主要组织储存库，有机体在繁殖生长和传播给新宿主方面最为成功。基于数十年的现场工作，人们普遍认识到许多菌株的组织部位偏好不同，从而产生了不同的喉咙和皮肤菌株的概念。这种认识强烈表明存在一种潜在的遗传组织，该组织赋予该物种的不同菌株更高的生物秩序。 A long-term goal is to determine the molecular basis for throat and skin tropisms among GAS. 在初步发现中，分析了多种喉咙和皮肤菌株的不同基因座/等位基因组合之间的连锁不平衡，从而鉴定出可能对组织特异性适应至关重要的基因。该提案的具体目标是在密切模拟人类浅表皮肤感染的体内小鼠模型中测试组织特异性毒力因子候选物的作用。将构建在皮肤菌株背景上具有咽喉基因的同基因突变体和嵌合 GAS 构建体并比较毒力。待测试组织特异性功能的 GAS 产品包括链激酶（纤溶酶原激活剂）、纤溶酶原结合 M 蛋白 (PAM)、半胱氨酸蛋白酶 SpeB 和 GAS 毒力基因表达的转录调节因子（RofA/Nra 和 Mga）。更好地了解喉咙和皮肤特异性感染的分子基础可能有助于开发针对基本适应性特征的疫苗，从而打破传播链。