Harnessing helminth-driven immunoregulation in the search for novel therapeutic modalities

Abstract

Parasitic helminths have coevolved with humans over millennia, intricately refining and developing an array of mechanisms to suppress or skew the host's immune system, thereby promoting their long-term survival. Some helminths, such as hookworms, cause little to no overt pathology when present in modest numbers and may even confer benefits to their human host. To exploit this evolutionary phenomenon, clinical trials of human helminth infection have been established and assessed for safety and efficacy for a range of immune dysfunction diseases and have yielded mixed outcomes. Studies of live helminth therapy in mice and larger animals have convincingly shown that helminths and their excretory/secretory products possess anti-inflammatory drug-like properties and represent an untapped pharmacopeia. These anti-inflammatory moieties include extracellular vesicles, proteins, glycans, post-translational modifications, and various metabolites. Although the concept of helminth-inspired therapies holds promise, it also presents a challenge to the drug development community, which is generally unfamiliar with foreign biologics that do not behave like antibodies. Identification and characterization of helminth molecules and vesicles and the molecular pathways they target in the host present a unique opportunity to develop tailored drugs inspired by nature that are efficacious, safe, and have minimal immunogenicity. Even so, much work remains to mine and assess this out-of-the-box therapeutic modality. Industry-based organizations need to consider long-haul investments aimed at unraveling and exploiting unique and differentiated mechanisms of action as opposed to toe-dipping entries with an eye on rapid and profitable turnarounds.

Fig 1. "Worm therapy" for immune dysregulation diseases.

The range of host physiological factors impacted by gastrointestinal helminth infection could alleviate inflammatory disease. (1) Parasite-derived factors drive an inclusive or exclusive polarized regulatory or type 2 response, which is responsible for (2) direct secretion of anti-inflammatory molecules from the host immune system (3) and the promotion of barrier integrity, which is often compromised in the pathophysiology of IBD and foodborne incompatibilities. Furthermore, (4) helminth colonization provides factors for a diverse bacterial environment that protects against gut inflammation. IBD, inflammatory bowel disease; T_H2, T helper type 2; Treg, regulatory T cell.

Fig 2. Inflammation and metabolic imbalance versus glucose homeostasis and weight loss, in response to infection with gastrointestinal nematodes and intravascular blood flukes and their ESPs.

Chronic inflammation in adipose tissue is linked to a switch to M1 macrophages and the production of TNF-α and IL-1β. Helminth infection and helminth ESPs induce changes in the gut that lead to a regulatory/T_H2 milieu that results in reduced inflammation in adipose tissue, enhanced glucose homeostasis, and decreased weight gain in obese animals. Furthermore, this regulatory/T_H2 milieu increases IL-33 produced in adipose tissue by stromal cells within the progenitors of both adipocytes and mesenchymal cells. The production of IL-33 induces resident ILC2 to produce IL-5, which recruits eosinophils. Eosinophils in white adipose tissue secrete IL-4, which induces M2 macrophages. The production of IL-33 also induces regulatory T and B cells to produce IL-10, which sustains M2 macrophage activity. ESPs, excretory/secretory product; IL, interleukin; ILC2, type 2 innate lymphoid cell; M1, classically activated macrophage; M2, alternatively activated macrophage; T_H2, T helper type 2; TNF, tumour necrosis factor.

Fig 3. Helminths and their ESPs manipulate the host immune system.

Helminth infection promotes T_H2 cell differentiation, Treg responses, macrophage polarization, and mucus production, which are regulated by multiple upstream events and stimulated by signals from the worm (ESPs), but also signals from the microbiome (metabolites) and tissue damage (alarmins). DCs are central to these processes and respond to alarmins, ESPs, and metabolites to adopt a regulatory phenotype that promotes Treg, Breg, and T_H2 cell development and suppress T_H17 and T_H1 cell responses. In addition, helminth-induced damage to the epithelium causes the release of alarmins such as TSLP, IL-25, and IL-33 from tuft cells and other epithelial cells, which can act on ILC2s and granulocytes to augment production of type 2 cytokines. This network is also influenced by sensory neurons within the gut that sense signals from helminths and microbes and elicit production of neuropeptides such as NMU and CGRP to regulate ILC2 responses directly. Breg, regulatory B cell; CGRP, calcitonin gene-related protein; DC, dendritic cell; ESPs, excretory/secretory product; ILC2, type 2 innate lymphoid cell; NMU, neuromedin U; T_H2, T helper type 2, TLSP, thymic stromal lymphopoietin; Treg, regulatory T cell.