Mucin glycans as novel immunoregulators of host response

Lead Research Organisation: Institute of Food Research
Department Name: Contracts

Abstract

This project investigates the molecular mechanisms underlying a novel role of mucins as immunoregulators of gut homeostasis. Mucins are heavily glycosylated proteins covering the gastrointestinal epithelium, providing a physical and biological barrier function against harmful molecules while maintaining a homeostatic relationship with our gut microbiota. In addition to this protective function, secreted mucins were recently shown to implement a biological signaling to suppress excessive host immune response whereby mucins bind to dendritic cells (DCs), a key regulator for the gut immune system, thus inhibiting cellular activation. This immunosuppressive effect was proposed to be mediated in vivo by two carbohydrate-binding proteins, Galectin-3 and/or Dectin-1, expressed on DCs, although direct evidence of binding remains to be determined. This project addresses the specificity and implication of mucin glycan-DC interactions at the molecular level by combining expertise from the Juge’s Lab in gut mucin biology and Kawasaki’s Lab in gut immunology, both having common interest and complementary expertise in carbohydrate-lectin interactions. We will characterize mucin-lectin interaction at the molecular level using atomic force microscopy and reporter cell-based assays and determine the immune response of human or mouse DCs in response to mucin treatment. Several outputs such as cytokine production and proliferation will be assessed by ELISA and flow cytometry. We will then investigate the carbohydrate structures on mucins responsible for the reported immunosuppressive effect by using mucins of different glycosylation signatures following a chemo-enzymatic approach. Since mucin glycosylation is altered in inflammation and cancer, defining the precise mucin glycan structures recognised by mammalian lectins to elicit a tolerogenic response is critical to understand the role of these interactions in health and disease.

Publications

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Leclaire C (2018) Molecular basis for intestinal mucin recognition by galectin-3 and C-type lectins. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

 
Description We have obtained mechanistic insights into how our immune system interact with our gut bacteria and with our epithelium lining. We have shown that bacterial and mucin glycans play a significant role in mediating these interactions. We have identified host lectins as receptors of the interaction and showed that glycosylation plays a key role in this process. These findings provide a structural basis for the role of mucins in mediating immune responses and new insights into the structure and function of major mammalian lectins. the work has been published in FASEB J. 2018.
Exploitation Route The novel mechanistic information may help design strategies to optimise communication between bacteria and immune system with beneficial effect to the host.
Sectors Agriculture, Food and Drink,Pharmaceuticals and Medical Biotechnology

 
Description Norwich Research Park (NRP) Bioscience Doctoral Training Partnership (DTP) programme
Amount £100,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2018 
End 09/2022
 
Description Norwich Research Park Bioscience Doctoral Training Partnership
Amount £100,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 10/2021