The genome scale metabolic model for Trichuris muris gateway to host pathogen interactions and therapeutic targets

Abstract

Trichuris trichiura, the human whipworm, stands as one of the most prevalent soil-transmitted helminths infecting humans. In laboratories, the closely related mouse whipworm, Trichuris muris, often serves as a model for whipworm research. Despite the extensive research on the immune response to the mouse whipworm, our understanding of the intricate biology of this parasite remains relatively limited. Germ free mice are resistant to T. muris infection showing the importance of the host microbiota in establishing an infection. However, mice mono colonised with Bacteroides thetaiotaomicron (Bt) can support an infection by T. muris indicating that single bacterium is sufficient for the viability of T. muris. Currently little is known about the metabolism of T. muris and how its metabolism is intertwined with that of the host and its microbiota. In this study, a comprehensive analysis was conducted on the genomes of Bt and T. muris to explore their metabolic interactions within the host intestine. The comparison of their metabolic pathways has revealed that Bt has more enzymes involved in the biosynthesis of amino acids, vitamins and cofactors compared to T. muris, suggesting that their interaction may rely on essential metabolites produced primarily by Bt. Genome-scale metabolic models have emerged as indispensable tools for unravelling the metabolic features of organisms, deciphering host-pathogen interactions, and identifying novel therapeutic targets for diseases. In this study, the development of iTMU798, the first genome-scale metabolic model (GSMM) for a whipworm, enabled us to elucidate the metabolic features of T. muris. The utility of this model for conducting simulations allowed me to predict essential enzymes for the whipworm’s survival. One such essential enzyme identified was thioredoxin reductase (TrxR) and this discovery was validated in vitro using the drug auranofin. Notably, when mice infected with T. muris were administered auranofin, there was a trend towards the reduction of worm burden, although statistical significance was not achieved. Moreover, iTMU798 predicted seven essential amino acids, a finding that was subsequently validated, indicating the impact of tryptophan absence on worm fecundity. Intriguingly, this research revealed that T. muris did not have glutathione reductase responsible for glutathione reduction, and TrxR in T. muris had the capacity to reduce the oxidised glutathione. This suggests a potential new mechanism for glutathione reduction. Furthermore, the identification of the nucleotide sequence of trxr-1 in T. muris enabled Tm-TrxR to be produced recombinantly, and its activity was reduced by auranofin. In summary, this study has demonstrated the reconstruction of the first whipworm GSMM, iTMU798, serving as a powerful platform for comprehending not only T. muris metabolism but also its metabolic interactions with the host and bacteria. Furthermore, the integration of omics data promises to provide new insights into the formulation of novel intervention strategies.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Richard Grencis (Supervisor) & Ian Roberts (Supervisor)