Dendritic cell interactions with capsular polysaccharides from extracellular bacteria: impact on innate & adaptive immune responses

感染通常发生在免疫系统无法对入侵的病原体做出最佳反应时，但将个体暴露于病原体衍生组分与增强免疫反应的试剂（称为佐剂）的组合是产生针对感染的强大免疫力的有效策略。因此，操纵免疫系统以产生针对病原体的有效免疫的探索可以被认为是现代免疫学的“重大挑战”。协调这种免疫的一个不可或缺的参与者是一种罕见但广泛分布的细胞网络，称为树突状细胞（DC）。DC被称为“天然佐剂”，表达病原体识别受体以感知和响应微生物或疫苗。过去十年的研究表明，DC在启动和控制免疫应答的质量和强度方面发挥着重要作用。因此，DC代表了疫苗学家有吸引力的免疫调节靶点，并且它们在控制宿主对细胞内病原体的免疫中的关键作用在很大程度上得到了证明。然而，关于DC在对细胞外细菌的免疫应答中的作用知之甚少，其中大部分被称为多糖胶囊（CPS）的糖壳覆盖，帮助细菌躲避免疫系统。一种这样的细菌是B族链球菌（GBS），其是西半球新生儿疾病和死亡的主要原因。CPS抗体对于保护免受感染至关重要，尽管这种反应的性质正在进行深入研究。CPS与载体蛋白的融合增强了其引发免疫应答的能力;然而，几个重要的问题仍未解决。在我的研究计划中，我建议描述GBS与DC的相互作用，以确定DC可以克服封装细菌逃避免疫系统所使用的策略的机制，从而启动保护性免疫反应。这些研究的数据将为包囊细菌引起的疾病的发病机制提供新的见解，从而有助于推进更有效的抗CPS疫苗的开发。这种疫苗的有效性将迫切需要最佳的DC应答，以产生持久的保护性免疫。

Infection often occurs when the immune system fails to respond optimally to invading pathogens, but exposing individuals to pathogen derived-components combined with an agent (called an adjuvant) that boosts immune responses is an effective strategy to generate robust immunity against infection. Therefore, the quest to manipulate the immune system to generate effective immunity against pathogens can be considered as the 'grand challenge' of modern immunology. An integral player orchestrating this immunity is a rare but widely distributed network of cells called dendritic cells (DC). DC, which have been called 'nature's adjuvants,' express pathogen recognition receptors to sense and respond to microbes or vaccines. Research in the last decade has shown a fundamental role for DC in initiating and controlling the quality and strength of the immune response. As such, DC represent attractive immune modulatory targets for vaccinologists and their critical role in controlling host immunity to intracellular pathogens is largely proved. However, much less is known regarding the role of DC in the immune response to extracellular bacteria, most of which are covered by a shell of sugars, known as the polysaccharide capsule (CPS), that help bacteria hide from the immune system. One such bacterium is Group B Streptococcus (GBS), a leading cause of disease and mortality in newborns in the Western hemisphere. Antibodies to CPS are crucial for protection against infection, although the nature of this response is under intense investigation. Fusion of CPS to a carrier protein enhances its ability to elicit an immune response; however, several important questions remain unsolved. In my research plan, I propose to delineate the interactions of GBS with DC to identify mechanisms by which DC can overcome the strategies used by encapsulated bacteria to evade the immune system and thus initiate a protective immune response. Data from these studies will provide new insights into the pathogenesis of the disease caused by encapsulated bacteria, thereby helping to advance the development of more potent anti-CPS vaccines. The efficacy of such vaccines will critically require optimal DC responses to generate a long-lasting, protective immunity.