Tissue-Specific Infection by Group A Streptococci

描述（由申请人提供）：A群链球菌（GAS）是最普遍的细菌病原体之一，仅感染人类。GAS的一个显著特征是菌株间的分子和生物多样性。虽然气体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，但大多数情况下，它只会引起浅表部位的轻微感染——口咽部（链球菌性咽喉炎）或表皮（脓疱疮）。咽喉和皮肤是GAS的主要组织储存库，因此生物体在繁殖生长和传播给新宿主方面最为成功。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上存在差异，从而产生了不同喉咙和皮肤菌株的概念。这种认识强烈地表明，有一个潜在的遗传组织赋予了这个物种的不同菌株更高的生物秩序。长期目标是确定GAS之间咽喉和皮肤趋向性的分子基础。

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.