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; TH2, T helper type 2; Treg, regulatory T cell.
Table 1.
Completed and ongoing therapeutic clinical trials using helminth products in humans in disease settings.
These trials are rigorously assessing the safety and tolerability of experimental helminth infection and therapeutic efficacy of infections in disease indications.
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/TH2 milieu that results in reduced inflammation in adipose tissue, enhanced glucose homeostasis, and decreased weight gain in obese animals. Furthermore, this regulatory/TH2 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; TH2, T helper type 2; TNF, tumour necrosis factor.
Fig 3.
Helminths and their ESPs manipulate the host immune system.
Helminth infection promotes TH2 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 TH2 cell development and suppress TH17 and TH1 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; TH2, T helper type 2, TLSP, thymic stromal lymphopoietin; Treg, regulatory T cell.