Host parasite interactions in Trichuris infections

Abstract

Infection with T. trichiura affects around 500 million people worldwide. Currently, no effective vaccines against worm infection are available to prevent infection of humans. The murine species of Trichuris, Trichuris muris, serves as an excellent model of human trichuriasis, and is used widely to study the host immune response against Trichuris. It is well documented that resistance to T. muris infection in mice requires a T helper 2 (Th2) type of immune response with T helper 1 (Th1) cells dominating in susceptible individuals. Understanding how Th2 immune responses are generated, is an unmet need which will facilitate vaccine development. It was previously thought that B cells are not essential for worm expulsion. However, our lab has recently shown that B cells play an important role in the generation of protective immunity. Thus B cells not only important in antibody production but also play a regulatory role in the generation of protective Th2 responses to Trichuris muris.

This PhD thesis explores the cellular sources of interleukin-10 (IL-10) during T. muris infection, focusing on subsets of T cells, macrophages, and B cells using the IL-10 reporter (Vert-X) mice. Follicular B cells and marginal zone B cells were found to be the main source of IL-10 in the mesenteric lymph nodes at day 21 post-infection. This pattern was shifted at day 35 post-infection, when B1a, B1b, and marginal zone B cells became the main IL-10 producers. These data suggest the importance of B cell-derived IL-10 in controlling immunopathology and facilitating long term immune regulation. In large intestine, follicular B cells were identified as the primary IL-10 producers in the lamina propria leukocytes at day 21 post-infection.

Building on these findings, the thesis goes on to investigate the role of B cell-derived IL-10 in immune responses and pathology in a low dose Trichuris muris infection using a transgenic CD19creIL10flfl mouse model that lacks IL-10 production in B cells. Notably, the absence of B cell-derived IL-10 made mice less able to support a chronic infection, without altering gut pathology. Interestingly, the absence of B cell-derived IL-10 was associated with a reduction in IL-6 mRNA and in some cases reduced IFN-γ levels in the gut, alongside an increased in FoxP3+ Treg cells. The study also extended to exploring the importance of B cell-derived IL-10 in the context of a high dose T. muris infection. No significant differences were identified between mice where B cells could and could not make IL-10 in terms of gut pathology and the kinetics of worm expulsion. However interestingly, in the absence of B cell derived IL-10 mice had high numbers of M2 macrophages in the gut tissue which correlated with non-significantly reduced levels of IFN-γ mRNA. This research has informed our understanding of the contribution of B cell-derived IL-10 to the host immunity to T. muris. It highlights the necessity for further investigation to understand the mechanisms by which the B cell-specific IL-10 deficient mouse presents with elevated intestinal numbers of Foxp3+ Treg cells and elevated M2 macrophages in the context of low and high dose T. muris infection respectively