Novel mechanisms of antihelminth immunity

• Main Author: Entwistle, Lewis James
• Published: University College London (University of London) 2018
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.747240

Intestinal helminths are highly prevalent worldwide, infecting approximately a third of the world’s population, causing significant host morbidity. With no current vaccines, a limited number of effective chemotherapeutic drugs available and the emergence of drug-resistant helminths, it is essential to further our understanding of the mechanisms of antihelminth immunity. Our current understanding of antihelminth immunity places the type 2 immune response at the forefront of protection, with type 2 cytokines orchestrating and activating a plethora of immune and non-immune cells to mediate parasite expulsion. The naturally occurring intestinal helminth Heligmosomoides polygyrus establishes a chronic infection in many inbred naïve mice, with resistance to a challenge infection established following drug-cure. This experimental model allows us to identify novel mechanisms of drug-induced resistance, relative to susceptibility. In this thesis, we utilised next generation sequencing technology to identify two novel mechanisms of antihelminth immunity. Firstly, we determined that the enzyme phospholipase A2 group 1B (PLA2g1B) is an endogenous anthelmintic, upregulated in intestinal epithelial cells of resistant mice. We demonstrated that PLA2g1B was essential for resistance to H. polygyrus and that PLA2g1B directly cleaves phospholipids off infective H. polygyrus larvae. Secondly, we identified that the microRNAs miR-99a-5p, miR-148a-3p and miR-155-5p were upregulated in mice resistant to H. polygyrus during infection and were also essential for functional immunity. In summary, we have identified and characterised two novel mechanisms of antihelminth immunity and propose a model of tissue memory, essential for acquired resistance to H. polygyrus.