Abstract

We previously reported the identification of a novel family of immunomodulatory proteins, termed helminth defense molecules (HDMs), that are secreted by medically important trematode parasites. Since HDMs share biochemical, structural, and functional characteristics with mammalian cathelicidin-like host defense peptides (HDPs), we proposed that HDMs modulate the immune response via molecular mimicry of host molecules. In the present study, we report the mechanism by which HDMs influence the function of macrophages. We show that the HDM secreted by Fasciola hepatica (FhHDM-1) binds to macrophage plasma membrane lipid rafts via selective interaction with phospholipids and/or cholesterol before being internalized by endocytosis. Following internalization, FhHDM-1 is rapidly processed by lysosomal cathepsin L to release a short C-terminal peptide (containing a conserved amphipathic helix that is a key to HDM function), which then prevents the acidification of the endolysosomal compartments by inhibiting vacuolar ATPase activity. The resulting endolysosomal alkalization impedes macrophage antigen processing and prevents the transport of peptides to the cell surface in conjunction with MHC class II for presentation to CD4(+) T cells. Thus, we have elucidated a novel mechanism by which helminth pathogens alter innate immune cell function to assist their survival in the host.

Highlights

  • We previously reported the identification of a novel family of immunomodulatory proteins, termed helminth defense molecules (HDMs), that are secreted by medically important trematode parasites

  • No fluorescence was observed in PBS-treated cells stained with the anti-His6 tag antibody (Fig. 2A), which confirms the specificity of the antibody for recombinant FhHDM-1

  • FhHDM-1 colocalized with cholera toxin subunit B (CT-B) on the surface of murine RAW264.7 macrophages, demonstrating that its association with lipid rafts is not confined to human cells

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Summary

Introduction

We previously reported the identification of a novel family of immunomodulatory proteins, termed helminth defense molecules (HDMs), that are secreted by medically important trematode parasites. Pathogen antigens phagocytosed by macrophages undergo partial proteolysis by lysosomal peptidases before being loaded onto major histocompatibility complex (MHC) class II molecules for presentation to CD4ϩ T cells [1], which thereby generates both effector and memory immune responses. AMPs share only limited sequence identity, they are broadly classified based on homologous secondary structure as cathelicidins (linear ␣-helical peptides), defensins (␤-strand peptides connected by disulfide bonds), and bactenecins (loop peptides) [4]. Despite such variation, HDPs/AMPs are generally cationic with hydrophobic faces [5, 6], which allows many of them to interact with, and disrupt, negatively charged microbial cell membranes [7]

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