Suppression of inflammation and tissue damage by a hookworm recombinant protein in experimental colitis

Abstract

Gastrointestinal parasites, hookworms in particular, have evolved to cause minimal harm to their hosts when present in small numbers, allowing them to establish chronic infections for decades. They do so by creating an immunoregulatory environment that promotes their own survival, but paradoxically also benefits the host by protecting against the onset of many inflammatory diseases. To harness the therapeutic value of hookworms without using live parasites, we have examined the protective properties of the recombinant protein anti-inflammatory protein (AIP)-1, secreted in abundance by hookworms within the intestinal mucosa, in experimental colitis. Colitic inflammation assessed by weight loss, colon atrophy, oedema, ulceration and necrosis, as well as abdominal adhesion was significantly suppressed in mice treated with a single intraperitoneal dose of AIP-1 at 1 mg kg−1. Local infiltration of inflammatory cells was also significantly reduced, with minimal goblet cell loss and preserved mucosal architecture. Treatment with AIP-1 promoted the production of colon interleukin (IL)-10, transforming growth factor (TGF)-β and thymic stromal lymphopoietin (TSLP), resulting in the suppression of tumour necrosis factor (TNF)-α, IL-13 and IL-17 A cytokines and granulocyte macrophage colony-stimulating factor (GM-CSF), CX motif chemokine (CXCL)-11 and cyclooxygenase synthase (COX)-2 mRNA transcripts. AIP-1 promoted the accumulation of regulatory T cells in the colon likely allowing rapid healing of the colon mucosa. Hookworm recombinant AIP-1 is a novel therapeutic candidate for the treatment of inflammatory bowel diseases that can be explored for the prevention of acute inflammatory relapses, an important cause of colorectal cancer.

Regulation of immunity and allergy by helminth parasites

“…Parasites have evolved multiple strategies to exploit the Treg pathway, including modulating DCs to drive Treg induction and IL‐10 production . In one recently reported example, hookworm Anti‐Inflammatory Protein (AIP)‐2 protein acts in mouse models through CD103 + DCs to expand Tregs; as a result, AIP‐2 administration can abate airway allergic inflammation as well as colitis induced by TNBS administration …”

Hookworm-derived small molecule extracts suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes

“…While iatrogenic infection with hookworms and other helminths shows promise for treating numerous inflammatory diseases in humans, the therapy presents many challenges including patient apprehension, safety concerns and regulatory hurdles (17, 54). We and others showed that A. caninum ES proteins (>10 kDa) have potent immunomodulatory properties and can protect mice against pathology in different inducible models of colitis (17, 19, 20, 55, 56) and asthma (22). Non-proteinaceous small metabolites derived from helminths, however, have received far less attention in terms of their molecular characterization and their immunoregulatory properties.…”

“…We previously characterized the protein constituents (>10 kDa) of hookworm ESP (21), and recently identified a single protein, Ac -AIP-2, which in recombinant form displays immunomodulatory properties in a mouse model of asthma that was dependent on regulatory T cells and tolerogenic dendritic cells (DC) (22). A related protein termed Ac -AIP-1 was recently shown to protect against inducible colitis by inducing accumulation of regulatory T cells in the mucosa and production of suppressor cytokines including IL-10 and TGF-β (23). Despite progress on the immunoregulatory properties of hookworm ES proteins, much less is known about the composition and anti-inflammatory properties of non-protein small metabolites or low molecular weight metabolites (LMWM; <10 kDa) in hookworm ESP (24).…”

Hookworm-Derived Metabolites Suppress Pathology in a Mouse Model of Colitis and Inhibit Secretion of Key Inflammatory Cytokines in Primary Human Leukocytes

“…While iatrogenic infection with hookworms and other helminths shows promise for treating numerous inflammatory diseases in humans, the therapy presents many challenges, including patient apprehension, standardization of treatment, and regulatory hurdles (17,32). In an effort to exploit the therapeutic potential of hookworms without the need to infect patients with live worms, we and others showed that hookworm ESP proteins (Ͼ10 kDa) have potent immunomodulatory properties and can protect mice against pathology in different inducible models of colitis (17,19,20,23,33) and asthma (22). Nonproteinaceous metabolites derived from helminths, however, have received far less attention in terms of their molecular characterization and their immunoregulatory properties.…”