Glucose and Amino Acid Catabolism in Plasma Cell Biology

Abstract: The usage of metabolic pathways is tailored to meet the specific functions and demands of a given cell type. Of particular interest is how metabolism supports the survival and antibody secretion of plasma cells, the primary cell type that is responsible for humoral immunity. The lifespan of these cells dictates the duration of antibody-mediated immunity after infections or vaccines—a particularly relevant topic in the midst of this pandemic. During the previous funding period, our work suggested a surprisingly minimal role for transcriptional pathways in controlling plasma cell lifespan. Instead, metabolic pathways functionally distinguish plasma cells of differing lifespans. Using newly created genetic tools, we will rapidly define and dissect essential plasma cell metabolic pathways in vivo. We will use newly generated plasma cell Cre-drivers, lentiviral bone marrow chimeras, and CRISPR/Cas9 approaches to functionally define mitochondrial dynamics, essential metabolic pathways, and vesicular maturation pathways that promote plasma cell lifespan and antibody secretion. These approaches will be coupled with sensitive imaging mass spectrometry and stable isotope-tracing experiments to provide mechanistic insight. Specifically, our experiments will define the importance of mitochondrial fission and fusion in plasma cell energy metabolism, antibody production, and survival. Physiological experiments using viral infections and immunizations will define key factors that promote plasma cell metabolic re-programming as these cells become progressively longer lived. Second, based upon results of a completed genome-wide CRISPR/Cas9 screen, we will pursue the importance of V-type ATPases in amino acid uptake, plasma cell lifespan, and antibody secretion in vivo.