Soil-transmitted helminths are a major cause of morbidity for humans and their livestock. A combination of better sanitation, anthelminthic drugs and vaccines are predicted to reduce the morbidity of these parasites in humans. The drugs currently used to treat these infections, albendazole and mebendazole, are fairly ineffective against Trichuris trichiura (human whipworm), and there are reports of drug resistance arising within parasite populations in Vietnam and Zanzibar. There are also no commercially available vaccines against human STH species, and very few against their veterinary counterparts. The murine whipworm, T. muris, has been used for over 50 years as a model for T. trichiura. These parasites share homology at the genomic and transcriptomic levels, and the immune responses associated with both acute and chronic infection have been well studied using the T. muris mouse model. T. muris excretory/secretory products have been studied in the context of vaccination for over four decades, however relatively little progress has been made towards identifying the molecular components that stimulate protective immunity following vaccination or during acute infection. Here, a stringent selection protocol was developed using chromatography and mass spectrometry methods combined with a measurement of T cell cytokine production. The work presented in this thesis provides a novel framework for identifying potential immunogenic candidates within adult T.muris excretory/secretory products. Exosome-like vesicles isolated from adult T. muris ES were also explored as a source of host protective material. Vaccination with exosome-like vesicles protected male C57BL/6 mice from a subsequent low dose infection, which would ordinarily progress to chronicity, and a number of potential immunogenic candidates were identified. Over the course of this thesis, several important observations were made relating to characteristics of the immune response induced by vaccination with ES. Firstly, proteinaceous material is likely to be responsible for the host protective properties of ES. Secondly, vaccination with ES products stimulates long-lasting immunity. Thirdly, vaccination with ES collected from both larval and adult stages stimulates protective immunity. The number of potential immunogenic candidates has also been narrowed down from over four hundred to just eleven. Given the homology between T. muris and T. trichiura at both the genomic and transcriptomic levels, this work has the potential to advance vaccine design for T. trichiura and other Trichuris parasites.

Trichuris trichiura is a gastrointestinal dwelling nematode that infects almost 500 million people worldwide. T. muris occurs naturally in mice and is very closely related the human whipworm, making it a suitable model to dissect the immune response against the parasite. Studies using the Trichuris muris system have identified CD4+ T cells as dictators of the outcome of infection. In wild type mice, infection with a high dose of T. muris eggs leads to resistance and worm expulsion, which are dependent on a Th2 response and the secretion of type 2 cytokines especially interleukin (IL) 13. Chronicity is dependent on a Th1 response and occurs when mice are infected with a low dose of T. muris eggs. It is well established that metabolic changes are essential to promoting T cell activation and effector function. Moreover, during chronic infection the host immune system is continuously exposed to parasite antigen, which represents a metabolic challenge. This thesis has investigated the importance of T cell metabolism during response against T. muris. Data presented here show that low and high dose T. muris infections promote upregulation of the glycolytic pathway in CD4+ T cells. During later stages of chronic infection, CD4+ T cells displayed supressed glycolysis and mitochondrial respiration, and may be due to metabolic modulation imposed by the parasite. Leucine uptake via the amino acid transporter Slc7a5 was previously shown to be required for mTORC1 activation and for T cell effector function. Data presented here show that in early stages following a high dose T. muris infection, mice that lack Slc7a5 in T cells have delayed worm expulsion, impaired production of antibodies, and lower levels of IL-13. Their CD4+ T cells present reduced glycolytic rates when compared to cells from cohoused infected wild type mice. However, at later stages of infection, antibody, IL-13 and glycolytic levels were restored together with worm expulsion. CD4+ T cells from the early stage of infection showed reduced phosphorylation of mTOR, which suggested that impairment of function was mTOR dependent. Indeed, mice lacking mTOR in T cells fail to expel a high dose of parasites. They showed abrogation of IL-13 production, impairment in antibody class switching and their CD4+ T cells failed to upregulate glycolysis. Thus, this thesis shows that mTOR is essential for the proper functioning of T cells during T. muris infection and efficient amino acid transport plays a significant role. Taken together, these data show that metabolic orchestration of T cell function influences the capacity to effectively control helminth infection and that even subtle changes in T cell metabolic control can have a major effect on response phenotype.