Grant: Project Grant

Macrophages and dendritic cells engulf microbes in order to remove these from our bodies. Once engulfed, the pathogen is sequestered within a new organelle called a phagosome, which matures into a digestive phagolysosome by fusing with lysosomes. Lysosomes are organelles that host digestive enzymes. These cells are also known as antigen-presenting cells (APCs) because they have a critical role in processing and presenting antigenic peptides, microbe fragments formed during digestion. Presentation of antigens activates T cells, which train the immune system to make antibodies against a specific microbe. Thus, antigen presentation and T cell priming are essential steps during vaccination. In resting APCs, lysosomes are vesicular. Yet, APC exposure to bacterial molecules transforms lysosomes into an expanded tubular network. We discovered that expansion of the lysosome system helps APCs take up more extracellular cargo, which seems to improve antigen presentation. We also found that lysosome expansion is driven by rapid activation of cellular machines that convert genetic information in the form of mRNA into proteins, a process called translation. In this project, we will precisely determine which pathways responsible for up-regulating translation are important for lysosome expansion and antigen presentation. We will apply a systems-biology approach to obtain a global understanding of how translation drives APC maturation. Lastly, we will identify adjuvants that remodel the lysosome system and if this is important for their immuno-potentiation. Adjuvants are substances added to vaccines to improve their efficacy and efficiency. Ultimately, this project uses a multi-disciplinary approach to examine how fundamental processes of information transfer within cells are used to adapt APC function to promote adaptive immunity. This knowledge may then provide tools to help boost the innate immune system and/or produce better and safer vaccines.