Immunoregulatory molecules secreted by Trichuris muris.

Allison J Bancroft,Richard K Grencis

doi:10.1017/s0031182021000846

Abstract

Trichuris, whipworm nematode infections are prevalent in humans, domestic livestock and mammals. All share an epithelial dwelling niche and similar life cycle with the chronic infections that follow implying that immune evasion mechanisms are operating. Nematode excretory secretory (ES) products have been shown to be a rich source of immunomodulatory molecules for many species. The Trichuris muris model is a natural parasite of mice and has been used extensively to study host–parasite interactions and provides a tractable platform for investigation of the immunoregulatory capacity of whipworm ES. The present review details progress in identification of the composition of T. muris ES, immunomodulatory components and their potential mechanisms of action. The adult T. muris secretome is dominated by one protein with modulatory capacity although remains to be completely characterized. In addition, the secretome contains multiple other proteins and small molecules that have immunomodulatory potential, certainly by comparison to other Trichuris species. Moreover, T. muris-derived exosomes/exosome-like vesicles contain both protein and multiple miRNAs providing an alternate delivery process for molecules with the potential to modulate host immunity.

Highlights

The mouse model of human diseaseTrichuris is a genus comprising intestinal nematodes including the human whipworm parasite, Trichuris trichiura, that is currently believed to infect approximately 465 million people worldwide causing considerable morbidity and economic hardship (Hotez et al, 2014; Pullan et al, 2014)
Trichuris muris has been used to inform on the complex interaction between the host, parasite and the rich microbial ecosystem that forms part of its niche
Low level infection with T. muris has been shown, in immunocompetent mice to result in changes in host pathology and a remodelling of the epithelial matrix

Summary

The mouse model of human disease

Trichuris is a genus comprising intestinal nematodes including the human whipworm parasite, Trichuris trichiura, that is currently believed to infect approximately 465 million people worldwide causing considerable morbidity and economic hardship (Hotez et al, 2014; Pullan et al, 2014). A study investigating the effects of helminth infection showed that it played a clear role in driving serum levels of zinc and iron in infected human populations independent of diet (Lee et al, 2019) The mechanisms underlying these observations are likely to be complex and involve parasite, host immunity and the intestinal microbiota as it is known that zinc and iron can influence immune function (Wessels et al, 2017) and the microbiota (Knezevic et al, 2020). Using a trickle infection approach in the laboratory, Glover et al (2019) showed that there was a steady build up in worm burden coincident with a dominant Th1 response until partial protective immunity was acquired due to the development of a stronger Th2 response This suggests that adult parasites are present before effective IL-13-mediated immunity is acquired and copious p43 is secreted into the intestinal niche, which would bind IL-13 from the developing Th2 response, effectively delaying host protection. The first demonstration of an involvement of type I IFNs in T. muris infection and Duque-Correra postulated that this immunosuppression may allow ELV cargo entry to the host immune system. White et al (2020) compared small RNAs in ELVs from T. muris and Heligmosomoides bakeri and found they were quite distinct from each other and concluded that this did not depend on their method of preparation but reflected their different intestinal niches and different functions within their hosts. Layton et al (2020) reviewed regulatory RNAs: miRNAs, siRNAs and piRNAs and advocated that miRNAs played a wider role than mere regulation of transcription of the host and were involved in communication between different taxonomic kingdoms including microbiota

Genomic analysis of potential novel immunomodulatory genes

Findings

Concluding remarks