Tissue-Specific Infection by Group A Streptococci

描述(申请人提供)：A组链球菌(GAS)是最常见的细菌病原体之一，仅感染人类。GAS的一个标志性特征是它在菌株中的分子和生物多样性。虽然气体会导致严重的疾病，如自身免疫性后遗症和严重的侵袭性疾病，但最常见的情况是，它只会导致浅表部位的轻微感染-口咽(链球菌喉咙)或表皮(脓疱疮)。咽喉和皮肤是气体的主要组织储存库，在这里有机体在生殖生长和向新宿主传播方面最成功。基于几十年的实地研究，人们已经广泛认识到，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应变的概念。这一认识强烈表明，存在一种潜在的遗传组织，赋予该物种的不同品系更高的生物秩序。一个长期的目标是确定GAS中喉咙和皮肤取向的分子基础。 在初步发现中，对一组不同的喉咙和皮肤菌株进行了分析，以确定不同基因座/等位基因组合之间的连锁不平衡，从而识别出可能对组织特异性适应至关重要的基因。这项建议的具体目的是在体内小鼠模型中测试组织特异性毒力因子候选者的作用，该模型非常接近于模拟人类浅表皮肤感染。将构建等基因突变体，以及具有皮肤菌株背景上的喉咙基因的嵌合气体构建体，并比较其毒力。将进行组织特异性功能测试的GAS产品包括链激酶(一种纤溶酶原激活剂)、纤溶酶原结合M蛋白(PAM)、半胱氨酸蛋白酶SpeB以及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特征的疫苗，从而打破传播链。

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.