INTRACELLULAR INFECTION BY INVASIVE GROUP A STREPTOCOCCI

严重的A组链球菌病的复发，包括败血症、中毒性休克和坏死性筋膜炎，已被彻底记录在案。虽然其他血清型与这些并发症有关，但流行病学数据表明，M1inv+亚克隆是20世纪90年代中毒性休克发生率增加的原因。我们的实验室是第一个发现M1克隆变异的人，这种变异最终传播到至少五个大陆。这个项目的总体目标是了解上皮细胞内入侵在A组链球菌高毒力菌株在人类群体中持续和传播中的作用。大部分研究将集中在M蛋白-细胞外基质蛋白、层粘连蛋白和纤维连接蛋白与上皮细胞之间的分子相互作用。实验将确定M1蛋白和其他噬菌体和染色体编码蛋白在人类细胞高频入侵中的作用。血管紧张素激动剂的功能将使用乳胶珠和扫描电子显微镜与其他链球菌因子分开进行分析。最后，体外对高频侵袭的要求将通过扁桃体器官培养来验证。这些研究可能为青霉素未能根除反复感染儿童口腔粘膜中的链球菌提供了解释。

The resurgence of serious group A streptococcal disease which includes sepsis, toxic shock and necrotizing fasciitis has been thoroughly documented. Although other serotypes are associated with these complications, epidemiological data argue that the serotype M1 inv+ subclone was responsible for the increased incidence of toxic shock in the 1990s. Our laboratory was the first to identify the M1 clonal variant that ultimately spread to at least five continents. The overall goal of this project is to understand the role of intracellular invasion of epithelial cells in the persistence and dissemination of highly virulent strains of group A streptococci in human populations. Much of the study will focus on the molecular interactions between M protein-extracellular matrix proteins laminin and fibronectin and the epithelial cell. Experiments will define the role of M1 protein and other bacteriophage and chromosomally encoded proteins in high frequency invasion of human cells. Invasin-agonist functions will be analyzed separate from other streptococcal factors using latex beads and scanning electron microscopy. Finally, in vitro requirements for high frequency invasion will be validated using tonsil organ cultures. These studies may provide an explanation for the failure of penicillin to eradicate streptococci from the oral mucosa of children with recurrent infections.