Kv1.3-Blocking Peptides from Parasitic Worms Exhibit Immunomodulatory Function

Abstract

Parasites have coexisted with their human hosts for thousands of years and are known mainly for their harmful disease-causing role in humans. However, probiotic worm therapy is beneficial in human autoimmune diseases, suggesting the existence of immunomodulators in parasitic worms. By screening a cDNA library and searching genome databases we identified a family of peptides in parasitic worms that share sequence similarity and evolutionary relatedness to potassium channel-blocking peptides secreted by venomous sea anemones. AcK1, a 51-residue secreted peptide of the hookworm Ancylostoma caninum, and BmK1, the C-terminal domain of a 413-residue zinc metalloprotease from the filarial worm Brugia malayi, share structural similarity to ShK and BgK peptides from sea anemones. These peptides block cloned and native human T-cell Kv1.3 channels at nanomolar to low micromolar concentrations. BmK2, an analog of BmK1, blocks Kv1.3 with an IC50 of 2 nM and exhibits >4000-fold selectivity for Kv1.3 over Kv1.1, Kv1.2, Kv1.6, Kv3.2, KCa3.1, K2P3.1. These peptides suppress proliferation of effector memory T cells that use Kv1.3 channels to regulate membrane potential, without affecting other T cell subsets that are not dependent on Kv1.3. They inhibit cytokine production and suppress the in vivo delayed type hypersensitivity response. Our results provide a mechanistic basis for pro-biotic worm therapy in human autoimmune disease, and suggest that these or related peptides and proteins could supplant the need for worm therapy.