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

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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.