Characterisation of Host- Parasite- Microbiota Interactions that Drive Hatching in Trichuris Species

Abstract

Trichuris trichiura infections account for 400 million individuals infected across the tropics and subtropics, making it a key neglected tropical disease (NTD). Infection occurs upon ingestion of whipworm eggs that hatch in the caecum and proximal colon, liberating larvae that establish in the intestinal epithelia. Trichuriasis has been studied in murine and porcine models of infection, with Trichuris muris and Trichuris suis respectively; revealing the role of the host intestinal microbiota in inducing hatching of whipworm eggs. However, the mechanisms behind the interactions between Trichuris species and the host microbiota that result in hatching, particularly in T. trichiura, remain unexplained. Understanding hatching could lead to greater control in the lab in maintaining T. trichiura life cycles, allowing us to use alternate more accessible hosts to study the human whipworm. I hypothesised that hatching in Trichuris spp, which is centered around the polar plugs of the egg, occurs as a result of physical interaction between the bacteria of the host microbiota and the parasite egg, and enzymatic activity that results in the degradation of the polar plugs and the liberation of the larvae. I isolated intrinsic and extrinsic factors that govern hatching in Trichuris species. In studying intrinsic factors in T. muris I discovered alterations in gene expression during embryonation that facilitate hatching, in particular serine proteases. I also examined the composition of the polar plugs to understand how they might be degraded in eclosion. In studying extrinsic factors in T. muris, T. suis, and T. trichiura I discovered that trichuris species preferentially respond to the microbiota from the parasite niche– the caecal mucosa, and that bacterial induced hatching of Trichuris species can be mediated by protease inhibitors. Furthermore, this study presents the first time a humanised microbiota model has been used to study in vitro hatching and in vivo infections of T. trichiura. In this study I isolated gastrointestinal samples that induce parasite hatching, and utilised metagenomic analyses to identify members of porcine, human, and humanised murine, microbiomes that could be responsible for inducing hatching of T. suis and T. trichiura, respectively.