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未能对入侵的病原体做出最佳反应时，但将病原体衍生的成分与一种增强免疫反应的试剂(称为佐剂)相结合，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对病原体的有效免疫力的探索可以被视为现代免疫学的重大挑战。协调这种免疫的一个不可或缺的因素是一种罕见但分布广泛的细胞网络，称为树突状细胞(DC)。被称为“天然佐剂”的DC表达病原体识别受体，以感知微生物或疫苗并对其做出反应。过去十年的研究表明，DC在启动和控制免疫反应的质量和强度方面发挥着重要作用。因此，DC对于疫苗专家来说是有吸引力的免疫调节靶点，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在胞外细菌免疫反应中的作用，人们知道的要少得多。胞外细菌的大部分被一种被称为多糖囊(CPS)的糖壳所覆盖，这种糖壳帮助细菌躲避免疫系统。其中一种细菌是B组链球菌(GBS)，它是西半球新生儿疾病和死亡的主要原因。针对CPS的抗体对于预防感染至关重要，尽管这种反应的性质正在密切研究中。CPS与载体蛋白的融合增强了其诱导免疫反应的能力；然而，仍有几个重要的问题尚未解决。在我的研究计划中，我建议描绘GBS与DC的相互作用，以确定DC可以通过哪些机制克服包裹细菌逃避免疫系统的策略，从而启动保护性免疫反应。这些研究的数据将为微囊化细菌引起的疾病的发病机制提供新的见解，从而有助于推动更有效的抗CPS疫苗的开发。这些疫苗的效力将至关重要地需要最佳的DC反应来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.