The immunomodulatory p43 secreted protein of Trichuris whipworm parasites is a lipid carrier that binds signalling lipids and precursors

Abstract

Parasitic helminths such as the Trichuris whipworms contribute to significant disease and morbidity in humans and other animals. They cause prolonged infections despite intact immune systems of their hosts, and their persistence is increasingly attributed to immunomodulatory activities of their secreted products. We examined the p43 (Tm-DLP-1) protein of Trichuris muris that comprises about 95% of the protein secreted by the adult parasite, is known to bind matrix proteoglycans, and have IL-13-neutralising activity. We show here that worm-derived p43 purified from secretions binds fatty acids and retinol, including signalling lipids or precursors thereof. This binding activity might therefore contribute to the parasites modulation of the infection site by delivering or sequestering influential lipids. A recombinant orthologue of p43 from the human whipworm, Trichuris trichiura (p47; Tt-DLP-1), has similar lipid-binding activity, with a similarly highly apolar biding site. From the known molecular structure of p43, we note the existence of extensive surface-accessible cavities with diverse surface charge characteristics which may indicate binding of a range of small molecule types in addition to lipids, and that its internally duplicated subdomains likely possess discrete characteristics. p43 belongs to the "dorylipophorins" that have only been found in Dorylaimia (Clade I) nematodes and appear to be the chief lipid carrier in their pseudocoelomic fluids, replacing the major lipid transporters of other nematode clades. In T. muris, and potentially other trichurids, these molecules appear to have been adapted for both internal physiological and external immunomodulatory activities.