Sc1 Proteins of S pyogenes: Biology and Function

A组链球菌(GAS)是世界范围内人类死亡和发病的主要原因。因此，了解GAS侵袭和侵袭宿主的分子机制对于开发新的抗链球菌疗法具有重要意义。很明显，细胞表面气体产物参与了疾病的发生。最近发现的两个链球菌基因，scl1和scl2，编码含有Gly-X-X胶原样重复序列的细胞表面蛋白。SCL的最后一个特征特别耐人寻味，因为抗链球菌细胞壁抗原的抗体与人类组织抗原发生交叉反应，导致感染后的自身免疫。然而，关于scl蛋白在体内的表达和宿主的抗原性尚不清楚。这项拟议工作的长期目标是确定scl在GAS黏附和侵袭人类细胞中的重要性，并评估抗scl反应在人类自身免疫性疾病中的作用。本项目将验证以下假设：(A)scl毒力因子参与了GAS的致病过程，(B)scl基因的表达受到各种调控机制的协调调节，许多GAS菌株同时产生scl1和scl2蛋白，以及(D)scl蛋白在体内表达，并由受感染的宿主产生抗scl特异性抗体。其具体目的如下：第一，通过构建GAS菌株的基因定义的等基因scl1和scl2突变体并在小鼠感染模型中测试它们，确定scl蛋白是否参与了GAS引起的不同疾病类型的发病机制；第二，确定scl蛋白是否有助于GAS与人培养细胞和细胞外基质成分的黏附；第三，确定scl基因表达的转录和翻译机制以及GAS菌株是否同时产生这两种scl蛋白；以及第四，分析scl蛋白在感染组织中的表达，以及在人血清和实验模型中产生抗scl特异性抗体。这些研究将为抗链球菌治疗的发展提供新的方向，并鉴于GAS表面胶原样抗原SCL的存在，可能对未来人类自身免疫性疾病的研究具有重要意义。

Group A Streptococcus (GAS) is a major cause of human mortality and morbidity worldwide. Therefore, understanding the molecular mechanisms by which GAS colonizes and invades human hosts is important for the development of new anti-streptococcal therapies. It is clear that cell surface GAS products participate in disease. Two recently identified streptococcal genes, scl1 and scl2, encode cell surface proteins that contain Gly-X-X collagen-like repeats. This last characteristic of Scl is particularly intriguing due to the fact that antibodies against streptococcal cell-wall antigens cross-react with human-tissue antigens, resulting in post-infection autoimmunity. However, nothing is known about Scl protein expression in vivo and antigenicity for the host. The long-term objective of the proposed work is to determine the importance of Scl in GAS adherence to and invasion of human cells and to evaluate the role of anti-SCL response in human autoimmune diseases. This project will test the hypotheses that (a) Scl virulence factors contribute to Gas pathogenesis, (b) expression of scl genes is coordinately regulated by various control mechanisms and many GAS strains simultaneously produce both Scl1 and Scl2 proteins, and (d) Scl proteins are expressed in vivo and anti-Scl-specific antibodies are produced by the infected host. The specific aims are as follows: First, determine whether Scl proteins participate in the pathogenesis of different disease types caused by GAS by constructing genetically defined isogenic scl1 and scl2 mutants of GAS strains and testing them in mouse infection models; second, determine whether Scl proteins contribute to GAS adherence to human cultered cells and extracellular matrix components; third, determine transcriptional and translational mechanisms controlling scl gene expression and whether GAS strains simultaneously produce both Scl proteins; and fourth, analyze expression of Scl proteins within infected tissue and production of anti-Scl-specific antibodies in human sera and in experimental models. The proposed studies will provide new directions for the development of anti-streptococcal therapies and, in light of the existence of the collagen- like antigen Scl on the surface of GAS, may have important implications for future studies of human autoimmune diseases.