Elucidating mechanisms underlying multivalency modulating lectin-glycan binding and assembly properties-implications for lectin function regulation

Pathogen surfaces display high density carbohydrates to shield underneath elements from being recognized by antibodies for immune evasion. To recognize the unusually displayed carbohydrate, in immune systems, carbohydrate binding proteins (known as lectins) form multimeric structures to cluster their binding sites. This also allows multiple contacts (multivalent binding) between them resulting in strong bindings similar to that observed with Velcro. Viruses and bacteria are much bigger than lectins, hence multiple lectins can bind to them, making the lectins further cluster together. As many lectins are attached to immune cells, the cluster can be interpreted as signalling to initiate immune defence. However, some pathogens have developed strategies to exploit such strong binding to facilitate their infection.

Currently, it is not clear whether they have changed the arrangement of carbohydrates to induce different lectin cluster patterns, and/or to make some binding sites on lectin unavailable for engagement which reduces binding strength and cluster stability, allowing more lectins to pack in to exclude other proteins from the area. These can be interpreted differently by immune cells. Here, we employ multidisciplinary approaches to address this question. We display synthesized pathogen carbohydrate fragments onto nanoparticle surfaces with different density, anchor multimeric lectins onto supported lipid bilayer and investigate how carbohydrate binding modulate lectin cluster/arrangement using high resolution imaging techniques. We further using lectin expressing immune cell to investigate how clustering regulates immune cell responses.

The project aims to deepen our understanding of immune signalling mechanism which provides guidance to develop treatments against infectious diseases, autoimmune diseases and also cancer.