Role and Control of IL-33 and Mast Cell Responses in Intestinal Helminth Infection

Helminth infections affect almost a quarter of the world’s population, and there is an increasing need for new anthelmintics. Interestingly, at a population level, there is an inverse correlation between the prevalence of helminth infections and allergic diseases such as asthma, and there is now evidence that helminths suppress the host immune system through the release of immunomodulatory molecules. Heligmosomoides polygyrus bakeri (Hpb) is a murine intestinal helminth that is useful as a model for human helminth infections. Hpb suppresses the host immune system via the secretion of immunomodulatory HpARI and HpBARI protein families. The HpARI proteins bind to IL-33, and the HpBARI proteins bind to the IL-33 receptor, ST2. This blocks IL-33/ST2 signalling which is important for the induction of the anti-parasite type 2 immune response. Suppression of ST2 detection has previously been described in peritoneal type 2 innate lymphoid cells (ILC2s) at day 7 of Hpb infection. In this thesis, I show that this suppression peaks between day 5 to 7 of Hpb infection, and ST2 detection reverts towards naïve levels by day 14 of Hpb infection. I show that this suppression also occurs on peritoneal mast cells. In addition, by using a vaccination approach, I show that this suppression is mediated by HpBARI proteins, and contributes to enhanced Hpb survival. Immunosuppression by Hpb also affects downstream and distal responses, including IL-33-mediated peritoneal neutrophilia, and lung immune responses to Alternaria alternata allergen. Finally, using mast cell-conditional ST2 knockout mice, I show that ST2 signalling on mast cells in particular is important in the anti-parasite immune response, as MCPT5Cre x ST2f/f mice lacking ST2 on mast cells show increased Hpb egg burdens. While the mechanism in which mast cell ST2 contributes to this phenotype has yet to be determined, intestinal RNA sequencing data suggests a role for tonic IL-33 signalling on mast cells in the maintenance of an intestinal neutrophil population.