INTRACELLULAR INFECTION BY INVASIVE GROUP A STREPTOCOCCI

严重的A组链球菌疾病，包括败血症，中毒性休克和坏死性筋膜炎的死灰复燃已被彻底记录。尽管其他血清型也与这些并发症有关，但流行病学数据表明，血清型M1 inv+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确定最终传播到至少五大洲的M1克隆变体的实验室。该项目的总体目标是了解上皮细胞胞内入侵在高毒力A群链球菌在人群中的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上。实验将明确M1蛋白和其他噬菌体及染色体编码蛋白在人类细胞高频侵袭中的作用。入侵激动剂的功能将与其他链球菌因子分开分析，使用乳胶珠和扫描电子显微镜。最后，利用扁桃体器官培养验证体外高频侵袭的要求。这些研究可能为青霉素不能根除复发性感染儿童口腔黏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.