Discussion

Various helminth parasites secrete molecules that modulate the immune responses of their hosts to benefit their survival. These molecules may not only be relevant targets for anti-parasite vaccine development, but could also have potential for the treatment of immune-mediated human disorders e.g. autoimmune diseases. During our on-going analysis of the secretory proteome of the Fasciola hepatica we identified a novel and abundant 8 kDa protein (68 amino acids). Immunohistochemical studies have shown that parasites secrete the molecule into host tissues as it migrates. Structural studies revealed that the 37 amino acid C-terminal region of the protein adopted a secondary structure (amphipathic α-helix) similar to a number of peptides with known antimicrobial and/or immunomodulatory functions, in particularly mammalian LL-37, and thus may act as a molecular mimic. Because of its ability to block the proinflammatory effect of endotoxin on macrophages we described this molecule as a helminth defense molecule, and termed it FhHDM-1. When added to macrophages in vitro, FhHDM-1 prevents acidification of the endolysosome. This prevents maturation of lysosomal cathepsin B protease and impairs the activation of NLRP3 inflammasome and the downstream production of IL 1β (which in vivo could block the development of protective Th1 type immune responses that are detrimental to parasite survival). This peptide ameliorated disease in two different in vivo murine models of autoimmunity, type 1 diabetes and relapsing-remitting immune-mediated demyelination. Phylogenetic studies have revealed that, so far, HDMs are expressed by trematodes but not by nematodes or cestodes. We have discovered a number of new HDMs in trematodes, which we expect will help us design more potent and effective immunomodulatory peptides for future vaccine/therapeutic applications.