Trickle infection and immunity to Trichuris muris
Open Access
- 15 November 2019
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 15 (11), e1007926
- https://doi.org/10.1371/journal.ppat.1007926
Abstract
The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data establish trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection. Infection with parasitic worms (helminths) is a considerable cause of morbidity in humans. Understanding how we respond to infection is crucial to developing novel therapies. Laboratory models of helminth infection have been a valuable tool in understanding fundamental immune responses to infection. However, typically an individual mouse will be infected with a large, single-dose of the parasite. This is in contrast to the natural scenario in which individuals will receive frequent low level exposures. However, it is unknown how repeated infection alters the development of immunity to infection. We have developed a laboratory model to tackle this question. We infected mice with the model helminth Trichuris muris on a weekly basis and assessed a range of responses in comparison with a more traditional infection regime. We found striking differences in the dynamics of the infection, the host immune response, and in changes to host gut microbial populations. Our study shows how resistance to helminth infection can develop over time in response to repeat infection, and provides a model system that better reflects human immunity to this parasite.Keywords
Funding Information
- Wellcome Trust (103131/z/13/z)
- Wellcome Trust (103132/z/13/z)
- Wellcome Trust (Z1066/Z/18/Z)
- Wellcome Trust (203128/Z/16/Z)
- Wellcome Trust (203128/Z/16/Z)
This publication has 64 references indexed in Scilit:
- Patent Human Infections with the Whipworm, Trichuris trichiura, Are Not Associated with Alterations in the Faecal MicrobiotaPLOS ONE, 2013
- Serine Protease(s) Secreted by the Nematode Trichuris muris Degrade the Mucus BarrierPLoS Neglected Tropical Diseases, 2012
- The intestinal epithelium tuft cells: specification and functionCellular and Molecular Life Sciences, 2012
- Muc5ac: a critical component mediating the rejection of enteric nematodesThe Journal of Experimental Medicine, 2011
- Mucin Gene Deficiency in Mice Impairs Host Resistance to an Enteric Parasitic InfectionGastroenterology, 2010
- QIIME allows analysis of high-throughput community sequencing dataNature Methods, 2010
- Helminth infections: the great neglected tropical diseasesJCI Insight, 2008
- Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tractThe Journal of Experimental Medicine, 2006
- The dynamics of trickle infections withAncylostoma ceylanicumin inbred hamstersParasitology, 1992
- Transfer of immunity against Trichuris muris in the mouse by serum and cellsInternational Journal for Parasitology, 1973