Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity

Abstract

Helminths are masterful immunoregulators. A characteristic feature of helminth infection is a Th2-dominated immune response, but stimulation of immunoregulatory cell populations, such as regulatory T cells and alternatively activated macrophages, is equally common. Typically, Th1/17 immunity is blocked and productive effector responses are muted, allowing survival of the parasite in a "modified Th2" environment. Drug treatment to clear the worms reverses the immunoregulatory effects, indicating that a state of active suppression is maintained by the parasite. Hence, research has focussed on "excretory-secretory" products released by live parasites, which can interfere with every aspect of host immunity from initial recognition to end-stage effector mechanisms. In this review, we survey our knowledge of helminth secreted molecules, and summarise current understanding of the growing number of individual helminth mediators that have been shown to target key receptors or pathways in the mammalian immune system.

Fig. 1

Helminth ES proteins: an example of the complexity of secreted proteins, from adult B. malayi, highlighting products discussed in the text. (A) One-dimensional gel, Coomassie Blue stained, showing selective secretion compared to whole somatic extract, indicating the migration of N-acetylglucosaminyltransferase (GlcNaTase), leucyl aminopeptidase (LAP, the homologue of ES-62), galectin, triose phosphate isomerase (TPI) and B. malayi homologue of macrophage migration inhibitory factor-1 (Bm-MIF-1). (B) Two-dimensional, silver stained gel, with the positions of the same proteins indicated.

Fig. 2

Mechanisms of immune modulation by helminth ES products (in bold) and defined molecules (in plain type) discussed in the text. Abbreviations: APC, antigen presenting cell; ASP, Ancylostoma secreted protein; BES, B. malayi ES; CPI, cysteine proteinase inhibitor (cystatin); HES, H. polygyrus ES; IPSE, IL-4-inducing principle of schistosome eggs; L-NES, larval N. brasiliensis ES; MIF, macrophage migration inhibitory factor; NES, adult N. brasiliensis ES; NIF, neutrophil inhibitory factor; Sm, Schistosoma mansoni; SPN, serine proteinase inhibitor (serpin); TLR, toll-like receptor; TGF, transforming growth factor; TES, T. canis ES.