The role of the GP2-IgA-microbiota interactome in intestinal homeostasis and disease

• Applicant: Dr. Johanna Kabbert
• Subject Area: Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 509089618

The gut is inhabited by a vast population of symbiotic bacteria (microbiota) that are essential to host health, immune system development and maturation. The host immune system is in a constant and mutualistic dialogue with the microbiota - a dialogue that is essential for gut homeostasis. Therefore, both dysbiosis and inappropriate immune responses may drive the development of pathology such as inflammatory bowel disease (IBD). A key immune response mediating host-microbiota interaction and preventing dysbiosis is the secretion of immunoglobulin A (IgA) into the gut lumen. While the importance of adaptive IgA-responses to gut homeostasis is well established, the role and mechanisms of action of innate host-derived factors remain poorly studied. In this project we will investigate the role of glycoprotein 2 (GP2) - a host-derived protein that, like IgA, is secreted into the gut lumen, however, the in vivo functions of GP2 are largely unknown. Strikingly, GP2 is also a major autoantigen in IBD, although why GP2 becomes an autoantigen in IBD remains unclear. Our preliminary results show that GP2 binds to a large proportion of the microbiota in both mice and humans, that GP2-bound bacteria are co-associated with IgA (but not IgG) and that levels of GP2-binding correlate with IgA-binding. Furthermore, GP2-deficient mice show an altered IgA-binding profile and overall changes in microbiota composition, particularly in the small intestine. Based on these findings, we hypothesize that GP2 represents a key innate modulator of host-microbiota interactions and may play an important role in intestinal homeostasis. In this proposal we aim to characterize the underlying mechanism regulating GP2-interactions with the microbiota, ist role in IgA-microbiota interactions and the importance of these interactions in mucosal immunity, intestinal homeostasis and disease. To assess this, we will utilize a wide range of multidisciplinary approaches including multiparameter flow cytometry, immunohistochemistry, bacterial cell sorting and 16S rRNA sequencing and mass spectrometry. We will make use GP2-deficient mice and established intestinal inflammation models to examine how GP2, IgA and the microbiota interact (at a population and cellular level). Knowledge gained from mouse experiments will allow us to expand our analysis on samples from healthy and inflamed human gut. Finally, we will examine the mechanisms leading to the generation of GP2 autoantibodies in chronic intestinal inflammation. Collectively, we anticipate the results of this project to substantially further our understanding of how innate immune mechanisms may converge with adaptive mechanisms to affect intestinal homeostasis and disease and as such will have important implications for both clinical diagnosis and novel treatment approaches for IBD.

• DFG Programme: WBP Fellowship
• International Connection: Sweden
• Host: Professor Dr. William Agace