Immunoregulatory molecules secreted by Trichuris muris

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.

Keywords: Immunoregulation; Trichuris; whipworm.

Graphical abstract

Fig. 1.

Modulation of protective immunity to Trichuris muris. A role for p43 secreted by adult worms through interaction with GAGs and IL-13. (A) Space-filled model of p43 highlighting TSP-1 and IL-13 Rα-2 homology (red). (B) Space-filled model of p43 docked with IL-13. (C) Diagrammatic representation of caecal epithelium overlaid by thick mucus shown in light green. A single adult worm is shown with anterior end embedded in the epithelium and posterior bulbous end free within the lumen. Chronic infection is IFN-γ driven and regulated by CD4⁺ Th cells producing IL-10. Secretion of copious p43 by adult worms is found within the worm niche and binds to extracellular matrix e.g. GAGs with high affinity. Repeated T. muris challenge infections following invasion of L1 larvae, as seen in trickle infections, begin to drive the generation of a Th2 response and the production of IL-13. GAG bound p43 will bind IL-13 with high affinity and prevent IL-13 effector function. The net result is a delay and reduced efficacy in host protective immunity, potentially enhancing parasite survival. Models of p43 courtesy of C. Levy.