Characterising Trickle Infection and Polyparasitism of Gastrointestinal Helminths

Abstract

Infection with gastrointestinal helminths is a significant cause of global morbidity. Given the challenges of investigating helminth infection in humans, murine models of infection have been central in defining the mechanisms that determine the outcome of infection. Two of the most well-characterised model helminths are the whipworm Trichuris muris and the hookworm Heligomosomoides polygyrus. The use of these parasites has cemented a critical role for Th2 immunity in the expulsion of parasitic nematodes. However, the majority of these studies have utilised experimental models in which single large boluses of an individual parasite are given, and analysis of subsequent immune responses are measured over a relatively narrow window of time. However, in situ individuals are more likely to be exposed to frequent re-infection, and are likely to be co-infected with multiple species. In this thesis both re-infection and co-infection were experimentally modeled. Trickle infection of H. polygyrus revealed that through multiple infections a more potent Th2 immune response develops that not only confers anti-larval immunity but also allows for a more rapid expulsion of adult parasites. This effect was dependant on ab-T cells. Co-infection of H. polygyrus and T. muris demonstrated that co-infection reduced resistance to T. muris. This correlated with the reduced cellularity of the colonic mesenteric lymph node and an increase in the fitness of adult female Trichuris worms. However, overt changes in canonical markers of resistance to T. muris remained unaffected suggesting the presence of as yet undefined modes of susceptibility and resistance to infection. During infection, an intimate relationship exists between the host, the parasite and microbiota, and it is thought that the microbiota plays an important role in directing host immune responses. However, there is a limited amount of data on the effect of helminth infection on the microbiome. Here a range of infection models were used to assess changes in the microbiota driven by helminths, these were then correlated with resistance and susceptibility to define bacteria groups connected to the outcome of infection. These include the Bacteroides and Escherichia-Shigella genera. Collectively the data presented here highlight a need for the adaptation of conventional infection models to better reflect natural modes of infection.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Richard Grencis (Supervisor)