The Untapped Pharmacopeic Potential of Helminths

doi:10.1016/j.pt.2018.05.011

Trends in Parasitology

Volume 34, Issue 10, October 2018, Pages 828-842

https://doi.org/10.1016/j.pt.2018.05.011 Get rights and content

Highlights

The current increase in the prevalence of immunological disorders is inversely correlated with the occurrence of helminth infections in highly developed countries.

The underlying protective helminth-mediated mechanism against immune-related diseases appears to be a shift in the proinflammatory Th1/Th17 immune response to a more balanced Th2/Treg immune profile.

Mouse models and clinical trials conducted with live parasitic worms or Trichuris suis ova have gained much attention as a possible treatment for immune-related diseases.

Worm-derived E/S products may serve as an important source of defined immunomodulatory molecules that can provide a safer and more controllable alternative for the treatment of immunological disorders rather than using unpredictable long-term helminth infections.

Apart from their immunomodulatory capacity, research has revealed other intriguing and exploitable activities of helminth-derived molecules.

The dramatic rise in immunological disorders that occurs with socioeconomic development is associated with alterations in microbial colonization and reduced exposure to helminths. Excretory–secretory (E/S) helminth products contain a mixture of proteins and low-molecular-weight molecules representing the primary interface between parasite and host. Research has shown great pharmacopeic potential for helminth-derived products in animal disease models and even in clinical trials. Although in its infancy, the translation of worm-derived products into therapeutics is highly promising. Here, we focus on important key aspects in the development of immunomodulatory drugs, also highlighting novel approaches that hold great promise for future development of innovative research strategies.

Section snippets

Helminth Infections – ‘World Wide Worms’

It has been estimated that at least 1.8 billion people are infected with helminths (see Glossary) [1]. Since helminth infections disproportionately affect low-income populations in developing regions of Africa, Asia, and America, they belong to a group of diseases referred to as the ‘major neglected tropical diseases’. According to the Global Burden of Disease Study 2016, helminth infections cause more than 10 million disability-adjusted life years (DALYs) [2]. Although highly parasitized

Immune-Related Disorders

Epidemiological studies have shown a rise in prevalence of immune-related disorders, including autoimmune and allergic diseases. Inflammatory bowel disease (IBD) [encompassing Crohńs disease (CD) and ulcerative colitis (UC)], type 1 diabetes (T1D), multiple sclerosis (MS), and rheumatoid arthritis (RA) are just a few examples of more than 80 autoimmune diseases that affect approximately 5–8% of the population worldwide, with the highest prevalence in the developed world [3]. Since these chronic

Worm Influences on Immunological Disorders

During millions of years of parasite–host coevolution, helminths have developed multiple mechanisms to modulate the host́s inflammatory responses and ensure their long-term survival in various hosts [5]. Not surprisingly, hundreds of immune-response genes were selectively favoured under the pressure of helminth infections [6]. Recently, a comprehensive meta-analysis of publicly available gene-expression datasets revealed a gene-expression signature across multiple helminth species and host

Helminth Therapy – ‘Domestication’ of the Worm

Worms as therapeutic agents have been applied in numerous animal models of diseases that have inflammatory or autoimmune etiology. Despite highly encouraging data from experimental animal models for IBD, MS, T1D, RA, and systemic lupus erythematosus that suggest preventive and therapeutic benefits [20], clinical trials in humans have lead to rather sobering results so far. For asthma and allergic rhinitis no benefit from helminth administration (Trichuris suis ova or hookworm infection) was

Hashtag # Helminth Therapy

Helminth replacement therapy as a form of probiotic therapy has gained much attention in mainstream media. Patients looking for alternative therapy for their maladies learn about helminth therapy through web-based community networks or social media [35]. There are multitudes of web sites promoting the therapeutic use of living parasites (‘worm smoothies’). Unfortunately, sometimes only self-treatment stories, case studies, or small clinical trials are presented that show beneficial responses to

E/S Products to Combat Immunological Disorders

Considering the biological complexity of metazoan parasites, using whole organisms or even purified protein fractions as therapeutic drugs is undesirable due to scalability and low stability as well as safety issues. Consequently, a less controversial and more palatable alternative to helminth therapy is the potential therapeutic use of helminth-derived immune-modulatory molecules.

Within their host, helminths release a rich mixture of proteins, glycoproteins, and low-molecular-weight compounds

Novel Therapeutic Approaches in Transfer and Delivery – ‘Signed Sealed Delivered’

The discovery of exosome-like extracellular vesicles that deliver bioactive macromolecules for intercellular communication has attracted considerable interest, particularly due to their role as mediators within the immune system [71]. EVs secreted by various helminths are effective vehicles for delivering proteins, lipids, and nucleic acids and other small molecules in a protected manner, thereby mediating cross-species communication as part of the host–parasite interaction [72]. The cargo of

Concluding Remarks and Future Perspectives

The remarkable advances in mass spectrometry-based proteomics have enabled the elucidation of whole secretomes (secretomics) from numerous helminths and have lead to the identification of the molecular components of the host–helminth interface. Furthermore, multitechnological integrative approaches that involve genomic, transcriptomic, and proteomic methods, combined with bioinformatics strategies, are producing a wealth of information at a very large scale, a valuable goldmine that serves as

Acknowledgments

We apologize to authors of primary literature for failing to cite their work directly owing to limitations in the number of references.

Glossary

Excretory–secretory (ES) products: helminths release a diverse mixture of proteins, glycans, and low-molecular-weight molecules considered to be readily exposed to the host́s immune system, many of which have immunomodulatory properties.
Group 2 innate lymphoid cells (ILC2): respond to IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), and produce early cytokines IL-13, IL-4, and IL-5.
Gut-on-a-chip: a 3D cell-culture model that mimicks key properties of the human gut, such as multicellular

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Immunomodulatory effects of parasites on autoimmunity
2022, Translational Autoimmunity: Treatment of Autoimmune Diseases
Some helminthic and protozoan infections become chronic with mild symptoms; however, they can gradually affect the immune system and skew its balance toward antiinflammatory conditions. Noticeably, infection with helminths is usually related to reduced cellular immune responses and a shift of T-cell responses to two types of T helper. An inverse association was also found between the prevalence of autoimmune diseases and helminthic infections which suggests that “helminthic therapy” might be beneficial in patients with autoimmune diseases. Helminthic therapy can mitigate the intensity of inflammatory responses and improve the clinical symptoms of autoimmune diseases with minor side effects. However, some intracellular protozoan infections will skew the immune responses toward T helper 1 type and may trigger the development of autoimmune disease. In this chapter, we will mainly focus on this idea and will discuss the possible mechanisms and also the challenges behind them. The main idea in helminthic therapy is the application of some parasites and their products as immunomodulatory agents for the development of new drugs and novel optimistic therapeutic agents for the treatment of autoimmune disease.
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However, main drawbacks are high production costs and demanding cultural conditions (Khan, 2013). While many of these heterologous systems have been successfully used to obtain soluble and bioactive helminth proteins for functional or immunological studies (Geldhof et al., 2007b; Kahl et al., 2018), the free living nematode Caenorhabditis elegans also has the potential to be an excellent host for the heterologous expression of ESPs. For nematode parasitologists C. elegans is a “user-friendly” model system to learn about the essentials of nematode biology.
The expression of antigens in their immunologically-active form remains a challenge, both in the analysis of regulatory pathways exploited by parasitic nematodes or in the development of vaccines. Despite the success of native proteins to induce protective immunity, recombinant proteins expressed in bacteria, yeast or insect cells offer only limited protective capacities, presumably due to incorrect folding or missing complex posttranslational modifications. The present study investigates the feasibility of using the free-living nematode Caenorhabditis elegans as an alternative expression system for proteins found in the secretome of parasitic nematodes. Exemplified by the expression of the extracellular superoxide dismutase from Haemonchus contortus (HcSODe) and the extracellular and glycosylated glutathione S-transferase from the filarial parasite Onchocerca volvulus (OvGST1), we continue our efforts to improve production and purification of recombinant proteins expressed in C. elegans. We demonstrate that sufficient quantities of functional proteins can be expressed in C. elegans for subsequent immunological and biochemical studies.
Oral delivery of a functional algal-expressed TGF-β mimic halts colitis in a murine DSS model
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There was an increase in all DSS-treated mice seen in the MLN (Supplementary Fig. 5B) but not the Peyer’s patches (Supplementary Fig. 5C). Immuno-modulatory parasites are increasingly recognized as treasure chests of novel, biologically active products with therapeutic potential, particularly for inflammatory disorders which are increasingly prevalent in industrialized societies (Johnston et al., 2009; Kahl et al., 2018; Maizels et al., 2018). Among the most severe of these “diseases of modernity” are inflammatory bowel diseases, for which no curative therapy is yet available (Kaser et al., 2010).
Inflammatory bowel disease (IBD) is a set of immunological disorders which can generate chronic pain and fatigue associated with the inflammatory symptoms. The treatment of IBD remains a significant hurdle with current therapies being only partially effective or having significant side effects, suggesting that new therapies that elicit different modes of action and delivery strategies are required. TGM1 is a TGF-β mimic that was discovered from the intestinal helminth parasite Heligmosomoides polygyrus and is thought to be produced by the parasite to suppress the intestinal inflammation response to help evade host immunity, making it an ideal candidate to be developed as a novel anti-inflammatory bio-therapeutic. Here we utilized the expression system of the edible green algae Chlamydomonas reinhardtii in order to recombinantly produce active TGM1 in a form that could be ingested. C. reinhardtii robustly expressed TGM1, and the resultant recombinant protein is biologically active as measured by regulatory T cell induction. When delivered orally to mice, the algal expressed TGM1 is able to ameliorate weight loss, lymphadenopathy, and disease symptoms in a mouse model of DSS-induced colitis, demonstrating the potential of this biologic as a novel treatment of IBD.
Onchocerciasis (river blindness) – more than a century of research and control
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In addition, the parasite synthesizes and releases a myriad of intercepting excretory/secretory (E/S) molecules, via extracellular vesicles or directly. These molecules include antioxidants, protease-inhibitors, carbohydrate- and lipid-binding molecules and cytokine regulators, which mitigate and detoxify the offending host's components and recently, in addition, have been suggested as possible immunomodulators suppressing inflammatory diseases (Hewitson et al., 2009; Ditgen et al., 2014; Kahl et al., 2018; Njume et al., 2019). O. volvulus microfilariae also release matrix-degrading serine and metalloproteases which can degrade components of the dermal extracellular matrix and elastic fibres of host tissue, as observed in chronic onchocerciasis (Haffner et al., 1998).
This review summarises more than a century of research on onchocerciasis, also known as river blindness, and its control. River blindness is an infection caused by the tissue filaria Onchocerca volvulus affecting the skin, subcutaneous tissue and eyes and leading to blindness in a minority of infected persons. The parasite is transmitted by its intermediate hosts Simulium spp. which breed in rivers. Featured are history and milestones in onchocerciasis research and control, state-of-the-art data on the parasite, its endobacteria Wolbachia, on the vectors, previous and current prevalence of the infection, its diagnostics, the interaction between the parasite and its host, immune responses and the pathology of onchocerciasis. Detailed information is documented on the time course of control programmes in the afflicted countries in Africa and the Americas, a long road from previous programmes to current successes in control of the transmission of this infectious disease. By development, adjustment and optimization of the control measures, transmission by the vector has been interrupted in foci of countries in the Americas, in Uganda, in Sudan and elsewhere, followed by onchocerciasis eliminations. The current state and future perspectives for control, elimination and eradication within the next 20–30 years are described and discussed. This review contributes to a deeper comprehension of this disease by a tissue-dwelling filaria and it will be helpful in efforts to control and eliminate other filarial infections.
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The human body contains a large number of microorganisms, and the gut microecology environment contains the largest number and types of microorganisms. The structure and function of gut microbiota are closely related to the health of the human body. In a cascade of studies, the diversity of gut microbiota and its metabolite often found changed in patients or mice model. What kind of gut microbiota that associated with the occurrence or treatment of diseases were also found in many studies. Gut microbiota and its products can affect the function of the human body. Short-chain fatty acids, bile acid, indoles and so on were found can regulate the inflammation, immune response to affect the process of diseases. Immune cells like natural killer T cells, CD3 + T cells were also found had a link to gut microbiota which associated with diseases. Changes in gut microbiota are associated with changes in the body's major systems, such as the digestive system, the endocrine system, the cardiovascular system, the endocrine and metabolic system, the urinary system diseases, the respiratory system and so on. It is of great significance to study gut microecology for the prevention and treatment of various human diseases.
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Through the years, helminths have co-existed with many species. This process has allowed parasites to live within them for long periods and, in some cases, to generate offspring. In particular, this ability has allowed Fasciola hepatica to survive the diverse immunological responses faced within its wide range of hosts. The vast repertoire of molecules that are constantly secreted in large quantities by the parasite, acts directly on several cells of the immune system affecting their antiparasitic capacities. Interestingly, these molecules can direct the host immune response to an anti-inflammatory and regulatory phenotype that assures the survival of the parasite with less harm to the host. Based on these observations, some of the products of F. hepatica, as well as those of other helminths, have been studied, either as a total extract, extracellular vesicles or as purified molecules, to establish and characterize their anti-inflammatory mechanisms. Until now, the results obtained encourage further research directed to discover new helminth-derived alternatives to replace current therapies, which can be useful for people suffering from inflammatory diseases like autoimmunity or allergy processes that affect their life quality. In this review, some of the most studied molecules derived from F. hepatica and their modulating capacities are discussed.

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Trends in Parasitology

OpinionThe Untapped Pharmacopeic Potential of Helminths

Highlights

Section snippets

Helminth Infections – ‘World Wide Worms’

Immune-Related Disorders

Worm Influences on Immunological Disorders

Helminth Therapy – ‘Domestication’ of the Worm

Hashtag # Helminth Therapy

E/S Products to Combat Immunological Disorders

Novel Therapeutic Approaches in Transfer and Delivery – ‘Signed Sealed Delivered’

Concluding Remarks and Future Perspectives

Acknowledgments

Glossary

Autoimmun. Rev.

Trends Immunol.

J. Neuroimmunol.

Gastroenterology

Trends Parasitol.

Acta Trop.

Int. J. Biochem. Cell Biol.

Protein Expr. Purif.

Mucosal Immunol.

Clin. Immunol.

J. Allergy Clin. Immunol.

J. Vaccines Vaccin.

Biochem. Biophys. Res. Commun.

Acta Trop.

Bioorg. Med. Chem.

Mol. Ther.

Kidney Int.

Mol. Biochem. Parasitol.

Int. J. Parasitol.

Trends Parasitol.

Med. Hypotheses

Immunity

Cell

Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016

Lancet

Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Lancet

Helminths in the hygiene hypothesis: sooner or later?

Clin. Exp. Immunol.

The landscape of human genes involved in the immune response to parasitic worms

BMC Evol. Biol.

Comprehensive transcriptome meta-analysis to characterize host immune responses in helminth infections

PLoS Negl. Trop. Dis.

Helminth infections decrease host susceptibility to immune-mediated diseases

J. Immunol.

Human helminths and allergic disease: the hygiene hypothesis and beyond

Am. J. Trop. Med. Hyg.

Influence of parasitic worm infections on allergy diagnosis in sub-saharan Africa

Curr. Allergy Asthma Rep.

Early life factors that affect allergy development

Nat. Rev. Immunol.

Asthma and current intestinal parasite infection systematic review and meta-analysis

Am. J. Respir. Crit. Care Med.

Reduced asthma morbidity in endemic areas for helminth infections: a longitudinal ecological study in Brazil

J. Asthma

Multiple sclerosis and the hygiene hypothesis

Neurology

Decreased prevalence of lymphatic filariasis among subjects with type-1 diabetes

Am. J. Trop. Med. Hyg.

Childhood helminth exposure is protective against inflammatory bowel disease: a case control study in South Africa

Inflamm. Bowel Dis.

The association between race and Crohn’s disease phenotype in the Western Cape population of South Africa, defined by the Montreal classification system

PLoS One

Helminth immunomodulation in autoimmune disease

Front. Immunol.

Experimental hookworm infection: a randomized placebo-controlled trial in asthma

Clin. Exp. Allergy

Helminth therapy (worms) for allergic rhinitis

Cochrane Database Syst. Rev.

Nematodes and human therapeutic trials for inflammatory disease

Parasite Immunol.

Helminth therapy (worms) for induction of remission in inflammatory bowel disease

Cochrane Database Syst. Rev.

A randomised, double-blind, placebo-controlled trial of Trichuris suis ova in active Crohn’s disease

J. Crohns Colitis

Safety, efficacy of helminth treatment in relapsing-remitting multiple sclerosis: results of the HINT 2 clinical trial

Opinion
The Untapped Pharmacopeic Potential of Helminths