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.

Helminth coinfection and COVID-19: An alternate hypothesis

“…This is particularly so should the mechanism of severe disease rest principally in endothelial invasion and vascular injury secondary to unchecked inflammatory responses, rather than ongoing viral replication. [ 12 ] Although the outcomes of trials have been mixed [ 13 ], experimental inoculation with the hookworm Necator americanus has been established as both practical and safe for use in study settings and has been successfully deployed in trials involving atopic and autoimmune disorders. [ 14 ] Importantly, no data exists studying the effect on metabolic outcomes, but one study is currently underway examining the effect of EHI on individuals with obesity and metabolic syndrome.…”

Metabolomes and Lipidomes of the Infective Stages of the Gastrointestinal nematodes, Nippostrongylus brasiliensis and Trichuris muris

“…l-citrulline, l-methionine, N(pi)-Methyl-l-histidine, succinate, and 4-hydroxybenzoate were the top five most abundant metabolites (based on LC-MS peak intensity) in the somatic extract and excretory/secretory products of N. brasiliensis L3. Succinate, one of the amino acids detected in the current study samples, is known to be produced by the intestinal microbiota to induce intestinal tufT cells to trigger T-helper cell type 2 (T H 2) responses [98]. Somatic and ESP of the adult stage of N. brasiliensis also contained succinate [21].…”

The Two Faces of Nematode Infection: Virulence and Immunomodulatory Molecules From Nematode Parasites of Mammals, Insects and Plants

“…Nematode-derived products are key to the immunomodulatory capabilities of the parasites, and investigating their mechanism of action may identify novel therapies for allergic and inflammatory diseases. Reviewing current research into which molecules show the most promise for the development of immunotherapies is an ongoing conversation that has already received a significant amount of attention ( Smallwood et al, 2017 ; Maizels et al, 2018 ; Bohnacker et al, 2020 ; Coakley and Harris, 2020 ; Ryan et al, 2020 ; White et al, 2020 ). Here we contribute to that conversation by contextualizing the most current advances in our understanding of immunomodulatory capabilities of nematodes and identifying the molecules that appear to show the most promise for further research.…”

“…Identifying the specific molecules within parasitic nematode ES or extract that have the strongest immunomodulatory potential is a main focus in the field of “helminth therapeutics” ( Ryan et al, 2020 ). Nematode-derived immunomodulatory molecules include mimics of host immune mediators as well as novel molecules that are unique to parasites themselves.…”

“…Several recent reviews have provided significant insight into the immunomodulatory role of nematode-derived molecules, in particular excreted and secreted proteins ( McSorley et al, 2013 ; Gazzinelli-Guimaraes and Nutman, 2018 ; Maizels et al, 2018 ; Zakeri et al, 2018 ; Maizels, 2020 ; Ryan et al, 2020 ). In this review, we highlight recently characterized nematode-derived molecules involved in host-parasite interactions, expand our discussion to non-protein molecules (e.g., lipids, nucleic acids) as potential for therapeutic targets, and investigate the utility of non-mammalian model systems (e.g., insect, plant) to understand host-nematode interactions.…”