Trichuris muris: a model of gastrointestinal parasite infection

Abstract

Infection with soil-transmitted gastrointestinal parasites, such as Trichuris trichiura, affects more than a billion people worldwide, causing significant morbidity and health problems especially in poverty-stricken developing countries. Despite extensive research, the role of the immune system in triggering parasite expulsion is incompletely understood which hinders the development of anti-parasite therapies. Trichuris muris infection in mice serves as a useful model of T. trichiura infection in humans and has proven to be an invaluable tool in increasing our understanding of the role of the immune system in promoting either susceptibility or resistance to infection. The old paradigm of a susceptibility-associated Th1 versus a resistance-associated Th2-type response has been supplemented in recent years with cell populations such as novel innate lymphoid cells, basophils, dendritic cells and regulatory T cells proposed to play an active role in responses to T. muris infection. Moreover, new immune-controlled mechanisms of expulsion, such as increased epithelial cell turnover and mucin secretion, have been described in recent years increasing the number of possible targets for anti-parasite therapies. In this review, we give a comprehensive overview of experimental work conducted on the T. muris infection model, focusing on important findings and the most recent reports on the role of the immune system in parasite expulsion.

Fig. 1

Trichuris muris life cycle. Infection occurs by the ingestion of infective eggs which hatch in the caecum 90 min post infection (p.i.) releasing the first larvae (L1). L1 penetrate the caecum and proximal colon wall, dwell in the epithelial layer and undergo three more moults to L2 (9–11 days p.i.), L3 (17 days p.i.) and L4 stage (22 days p.i.). By day 32 p.i. female and male adult forms of T. muris can be observed in the caecum and proximal colon of infected mice. Eggs, which leave the host organism with faeces, need 2 months to embryonate and become infective

Fig. 2

Epithelial cell turnover. Epithelial cells proliferate at the bottom of the crypt in the proliferation zone and subsequently migrate up the crypt through transit zone. When they reach the top of the crypt (shedding zone), they are removed. In resistance, mice infected with T. muris have accelerated epithelial cell turnover hindering worm ability to stay in the crypts attached to the epithelium. With faster epithelial cell turnover the parasite is moved to the top of the crypt, detached from the epithelium with shedded epithelial cells and subsequently expelled

Fig. 3

Mechanisms of T. muris expulsion. In resistance, generation of a Th2-type of a response is characterised by increased production of IL-4, IL-9 and IL-13. Basophils (Baso) and innate lymphoid cells (ILC) have been suggested to act as an early source of Th2 cytokines and to facilitate a Th2-type response development. Both increased epithelial cell (EC) turnover and increased production of mucins have been shown to be IL-13-dependent. Up-regulation of mucin secretion results in the thickening of a mucus layer which makes it more difficult for the parasite to stay attached to the epithelium. Also, mucus of resistant animals is rich in mucins such as Muc5ac which have a direct detrimental effect on worm viability. Moreover, IL-9 induces an increase in muscle contractility in the gut facilitating parasite expulsion. On the contrary, in susceptibility development of a Th1 response and production of IFN-γ result in slower EC turnover and muscle contractility, decreased Muc2 and lack of Muc5ac production. Furthermore, an exacerbated Th1 response eventually leads to immunopathology development resembling colitis. In addition, regulatory T cells (Treg) have been implicated in promoting susceptibility to infection with T. muris