Molecular and Cellular Interactions in Helminth Infections

The proposed research aims to (i) build fundamental understanding of mechanisms of immune evasion by helminth parasites, (ii) explore helminth modulation of the intestinal tissue niche; and (iii) to develop a new strategy towards vaccination to prevent infection. Helminths exploit a key immunological pathway within the immune system to induce suppressive regulatory T cells, and dampen innate effector cells. We have discovered a key player to be a novel parasite mimic of TGF-beta (TGM), which we will analyze structurally and funtionally on (i) immune cells and (ii) intestinal epithelium. The intestinal environment will be modelled through organoids (enteroids) in which parasites can modify stem cell differentation and therefore epithelial composition; we will investigate whether this is caused by TGM or an unrelated mediator. To promote immunity to infection, we focus on extracellular vesicles (EVs) released by parasites, which we have shown inhibit innate cell activation but can be neutralised by specific antibodies. In this model, antibodies to EVs direct them to uptake by phagocytes and lysosomal degradation, abolishing the inhibitory effect on immune cells. Taken together, the research will define how helminths may modify host signals and pathways, and how we may best interrupt this process to achieve protective immunity.