Tissue-Specific Infection by Group A Streptococci

描述（由申请人提供）：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，如自身免疫性后遗症和严重的侵袭性疾病，但它通常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）。咽喉和皮肤是GAS的主要组织储存库，因此生物体在生殖生长和传播到新宿主方面最成功。基于几十年的野外工作，人们已经广泛认识到，许多菌株在其组织部位偏好方面存在差异，从而产生了不同咽喉和皮肤菌株的概念。这种认识强烈表明，有一个潜在的遗传组织，赋予更高的生物秩序，以不同的菌株，这一物种。长期目标是确定GAS中咽喉和皮肤向性的分子基础。 在初步研究结果中，分析了一组不同的咽喉和皮肤菌株的基因座/等位基因的不同组合之间的连锁不平衡，从而确定了可能对组织特异性适应至关重要的基因。本提案的具体目的是在体内小鼠模型中检测组织特异性毒力因子候选物的作用，该模型非常模拟人类浅表皮肤感染。将构建在皮肤菌株背景上具有喉基因的同基因突变体和嵌合GAS构建体，并比较毒力。要测试组织特异性功能的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和GAS毒力基因表达的转录调节因子（RofA/Nra和Mga）。更好地了解咽喉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。

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.