Trickle infection and immunity to Trichuris muris

Abstract

Trichuris trichiura is a gastrointestinal helminth infection causing global morbidity and economic burden. The mouse species Trichuris muris is a well established laboratory model to study infection and immunity. Studies investigating the immune response to T. muris revealed that resistance is dependent on CD4+ Th2 cells and the production of IL-13 that mediates worm expulsion mechanisms. The majority of experimental studies follow infection and immunity after a single dose infection, however individuals are naturally infected with repeated low doses resulting in the slow development of partial immunity. Therefore to replicate a more natural infection regime in the laboratory, mice were infected repeatedly with low doses of T. muris, so called trickle infection and the developing immune response was investigated. Trickle infection of C57BL/6 mice resulted in the slow build up of worm burden followed by a significant decrease in adult worms and early larval stages, thus partial immunity was established. Flow cytometry revealed that a reduction in worm burden was associated with an increase in CD4+ Th2 cell populations that coincided with an increase in IL-13 and worm expulsion mechanisms, including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turnover. Depletion of CD4+ T cells confirmed their importance in the development of resistance following trickle infection. Challenge experiments confirmed that resistance developed following trickle infection was long lasting. Additionally, trickle infection resulted in a microbiome dysbiosis that recovered following the development of resistance. Group 2 innate lymphoid cells (ILC2s) have been shown to be essential for resistance following N. brasiliensis infection, therefore ILC responses were investigated during T. muris infection. Analysis of ILC populations by flow cytometry during single dose and trickle T. muris infection suggested there was no significant response during infection. Depletion of ILC2s in ICOS-T mice confirmed they were not essential for the development of resistance following a single high dose T. muris infection or a T. muris trickle infection. Together the data presented here demonstrates the need for natural infection regimes to be used in the laboratory for animal helminth models to become more applicable to human infections.

Date of Award	31 Dec 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Richard Grencis (Supervisor) & David Thornton (Supervisor)