IgA-Glycosylation: Mediator of Microbial Homeostasis and Intestinal Health?

Project SummaryImmunoglobulin A is the primary isotype secreted at mucosal surfaces and plays an important role in regulatinggut microbiota composition and enforcing host-microbiota symbiosis. The long-term goal of the proposedresearch is to understand how IgA mediates these important effector functions, and to resolve the paradox ofhow IgA targeting can support the growth of certain gut microbes, while restricting the growth of others. We willexplore the hypothesis that differential glycosylation of IgA can program unique antibody effector functions andimbue this important secretory isotype with divergent effects on gut microbiota composition. Although the roleof glycosylation in regulating IgG function is now abundantly clear, almost nothing is known about howglycosylation regulates the effector function of secretory IgA in the intestine, which exhibits even more complexand extensive glycosylation patterns than IgG. Our proposal addresses this paradox by examining IgAglycosylation patterns under a variety of inflammatory versus immunoregulatory conditions, and attempting toconnect changes in glycosylation to specific effects on microbial community structure. In Aim 1 we will examinepatterns of IgA glycosylation via lectin-based analyses, and through chromatography and mass-spectrometry.We will compare IgA glycosylation in mice with a `healthy' microbial community, as well as mice with acolitogenic `dysbiosis'; mice with and without T cells; and germ-free mice monocolonized with either Treg-inducing or Th17-inducing bacterial species. In Aim 2 we will construct mice in which only B cells lack criticalglycosyltranferase enzymes to examine the effects of aberrant glycosylation of IgA on shaping of the microbialcommunity in the gut. The successful completion of these aims will result in the first full characterization of IgAglycosylation in the gut, and may resolve an apparent paradox regarding the divergent effects of IgA coating oncolonization by and growth of specific gut microbes with inflammatory versus immunoregulatory capacities.Understanding the role of glycosylation in IgA effector function is necessary to empower potential therapeuticapproaches that aim to use IgA to reshape microbial communities. Finally, these studies may lay thefoundation for a broader program exploring the role of secretory IgA glycosylation in human health anddisease.