What are helminth parasites?
Helminths, or helminth parasites, are a group of multicellular worm-like parasites, some of which can be the cause of infectious disease in humans.
Helminths live inside the host and are known as endoparasites, whereby they often develop delicate but complex relationships with the human host at each stage of development. Therefore, worms which are ectoparasites, meaning that they live on the outside of hosts (such as leeches), are not considered to be helminths.
There is little consensus into how many phyla the helminths can be separated into, with some researchers saying that there are two or three phyla. So what are these categories called?
1. Flatworms (platyhelminthes)
These helminths are non-segmented, lack body cavity and are generally found in freshwater and marine environments, although they can also be occasionally found on land. Non-segmented worms’ bodies are not separated into sections (segments) and so do not have lines on them, unlike earthworms, for example. Flatworms also lack a body cavity, meaning their digestive system is not separated from the outer wall of their body. With the exception of a few species, flatworms are hermaphroditic, meaning that they do not have separate sexes. About 20,000 species have been described, but it is thought that the species diversity could be far greater than 100,000 variants
2. Roundworms (nematodes)
These creatures are slightly more complex than flatworms. Roundworms have a body cavity but, similarly to flatworms, are non-segmented and lack appendages (i.e. protrusions from their body). They are found in a huge variety of habitats and have the ability to infect plants, animals, and humans. Similarly to flatworms, approximately 20,000 species of roundworm have been described, but it is estimated that there are between 100,000 and 10,000,000 different species
3. Spiny-headed worms (acanthocephala)
As adults, spiny-headed worms are found only in the small intestine of vertebrates. Their heads are covered in many retractable spines which help to anchor the worms into the wall of the small intestine of the host. This is a much smaller phyla, with just over 1,000 known species
There are numerous species of helminth parasites which are of costly medical and economic significance, whilst some are parasitic to humans.
In fact, did you know roundworms that infect plants are estimated to cause 8-15% crop loss, costing about $80 million (or maybe more)?
Meanwhile, it is estimated that two billion people are currently infected by helminths, particularly in developing countries. Generally, helminth infections do not cause severe illness, and many human hosts can be largely asymptomatic. However, there are some instances where helminths (usually where there are a lot of worms) can cause severe disease, often nutritional deficits such as anaemia or slowed growth development, fatigue and diarrhea. In addition, they can also cause fast and unintended weight loss.
Helminths go through several stages of their life cycles (usually three or four as there can be differences in maturity of the larvae) and can live in a number of hosts throughout their lives. In some cases, this can be two or more different species. In essence, their life cycle can be split into eggs, larvae, and adults. However, the stages of the life cycle and the hosts which the helminth can infect can vary greatly between different species.
Figure 1: Generic helminth life cycle (in relation to humans). Helminths begin as eggs and these survive in the external environment. Following this, they become larvae, in which they either enter the human host through an entry point (such as through the mouth) or will exist in an intermediate host species. Finally, the helminth parasite will mature into an adult and produce eggs in the definitive host. During its time in the intermediate host, the helminth will pass through several stages of its life cycle where it is asexual and unable to reproduce. By contrast, the definitive host is where the helminth reaches sexual maturity and is able to reproduce. Eggs are then excreted, often through faeces, and the life cycle repeats itself. It is important to note that the intermediate and definitive host can be the same (i.e the helminth lacks an intermediate host), but it is likely that the larvae and adult helminths will be present in different tissues/parts of this host.
Our immune response against helminth parasites
To start with, it is important to understand the differences and key players in the type-1 (Th1) and type-2 (Th2) immune responses.
The Th1 response is associated with pro-inflammatory mechanisms (i.e. they cause inflammation), and is generally the first response to viral and bacterial infections. The main cytokines (i.e. signalling molecules that are specific to the immune system) associated with this response include IFN-γ, LTB and IL-2. It is thought that Th1 cytokines inhibit the Th2 immune response, thereby leading to chronic disease.
On the other hand, the Th2 immune response is associated with the protective immunity (protection against infection) against helminth parasites. It begins in the gut with the activation of a variety of cell types, including dendritic cells, basophils, innate lymphoid cells and other non-immune cells, such as intestinal epithelial cells. To put it simply, these cells will release type 2 cytokines, which go on to activate T helper 2 (Th2) cells.
Figure 2: A simplified diagram illustrating the Th2 immune response. After intestinal epithelial cells are damaged by a helminth infection, they release the cytokines IL-25, IL-33 and alarmins. IL-25 and IL-33 will then go on to activate innate lymphoid cells, which in turn release IL-13. After tha, IL-13 will cause the activation of Th2 cells. Alarmins, such as TSLP, activate dendritic cells and basophils. In turn, dendritic cells are able to induce Th2 cell differentiation, whilst basophils produce IL-4 to activate Th2 cells. These Th2 cells can then produce a range of cytokines, most importantly IL-13 and IL-4, which activate a huge number of processes to get rid of the parasite. Besides that, the helminth-specific IgE, a type of antibody, is also produced by B cells (which is activated by cytokines that are produced by Th2 cells). These cytokines are shown in red whereas the different types of cells are shown in black. Additionally, the stars next to IL-13 and IL-4 showcase that they are the key players in the Th2 immune response. This figure is adapted from Allen & Maizels (2011) and Cortés et al. (2017).
Typically, helminths cause a Th2 immune response, meaning it is mostly mediated by Th2 cells. The Th2 response also provides a way for the host to combat the parasite, whilst limiting damage to their own cells that would have been incurred if the type-1 immune response was deployed.
Helminths are also able to produce compounds that make them capable of avoiding the host immune system. For example, helminths are able to activate regulatory dendritic cells, macrophages and regulatory T cells (Tregs), which then go on to repress activity of cells involved in inflammatory responses. In particular, IL-10 and TGF-β are typically associated with this immunoregulatory response, and it has been suggested that IL-10 is essential in the suppression of an inflammatory environment.
To summarise, during helminth infection, our bodies aim to strike a balance between the clearance of any parasites (in order to protect ourselves against serious diseases) and the damage to our own cells if a highly inflammatory response is mounted against the parasite during this process. This is done by the Th2 immune response and its associated immunoregulatory mechanisms.
Introducing the hygiene hypothesis
In developed countries, having exposure to parasites and other microorganisms has decreased dramatically. This is because concurrently, modern sanitation and healthcare has drastically improved. Though ironically, there is also a much greater prevalence of chronic inflammatory disease in these countries.
To dive into greater detail, chronic inflammatory disease is a type of condition where our body begins to attack itself as it falsely recognises its own cells or a non-harmful substance (such as pollen when it comes to hayfever) as something foreign and dangerous. Such examples include autoimmune diseases (e.g. Crohn’s disease, multiple sclerosis, type-1 diabetes) and allergies, but also certain neuropsychiatric disorders like major depressive disorder and chronic fatigue syndrome.
With that in mind, this brings us to the discussion of the hygiene hypothesis. This hypothesis essentially proposes that the lack of exposure to infectious microorganisms causes an increase in the number of chronic inflammatory disease cases.
Figure 3: The hygiene hypothesis explained as an illustration. In areas with less access to healthcare and hygienic practices (such as modern sanitation), people are exposed to a greater number of disease-causing microorganisms (including helminth parasites). But interestingly, in these areas, there is also lower incidence of chronic inflammatory disease. At the same time, in areas where there are better sanitation measures, greater access to healthcare, people are generally exposed to a lower number of disease-causing microorganisms from an early age. Nonetheless, there is a higher incidence of chronic inflammatory disease in these areas. So, there appears to be an inverse correlation between the exposure to microorganisms and chronic inflammatory conditions.
Why exactly is this the case?
There are several suggestions that could potentially explain why having exposure to microorganisms (such as helminth parasites) decreases the prevalence of chronic inflammatory diseases. The popular theories would be that chronic inflammatory diseases are often dealt with in human hosts by the Th2 immune response, just like for helminth infections.
For those reasons, it is thought that helminths are involved in “training” our immune system to have appropriate responses to foreign agents and itself, given that helminths have also evolved alongside humans for hundreds, if not thousands, of years.
Helminth therapy as a medical treatment
It has been suggested that helminths or helminth-derived products could be used to treat chronic inflammatory conditions. This is because they have the ability to respond to and reduce inflammation and have a significant influence on our immune system.
A lot of the time, helminth-derived products have been largely preferred over the use of live helminths for several reasons.
Being able to avoid the potential spreading of helminth parasites into the environment. If they were to spread into the environment, for example, if hygienic practices (e.g. constant handwashing), they would uncontrollably infect other humans.
Preventing any unexpected spreading throughout the patient, as this could lead to disease and very bad side effects
Mitigating the challenges faced when producing live helminths that do not have pathogenic microbes in their growth environment. Because the helminths will be ingested by a patient, it is essential that the helminths do not harbour any pathogens that could cause disease in humans. If they did, they could cause greater harm to a patient than good.
Although there are technically ways to overcome the issues listed above, helminth-derived compounds are ultimately deemed to be the safer option.
It is also known that helminths affect the gut microbiome. In fact, without them, the balance of gut flora could be thrown off and this can cause chronic inflammatory conditions. The immune-regulating molecules that helminths produce could act against an overactive immune response. For example, cystatin, a potent protease, is able to induce Treg expansion and increase IL-10 production. This is done by increasing the Th2 immune response and dampening the Th1 immune response.
Although much of the evidence that we have that helminth therapy could work is based on disease models and clinical trials performed on animals, there have been several studies conducted in humans that also show promising results.
When carrying out these studies, it is important to ensure that a comprehensive health check has been made before the experiment. Meanwhile, researchers ought to always closely monitor any other health conditions the patients may have throughout the investigation.
At the point of writing, two species of helminth parasites have been tested for live helminth therapy, namely Trichius suis (T. suis) and Necator americanus (N. americanus).
T. suis is a type of roundworm that is infectious at its larval stage. Four patients, with Chron’s disease, a type of inflammatory bowel disease, and three with ulcerative colitis, another type of inflammatory bowel disease, were given live T. suis eggs every two weeks for 12 weeks and they were monitored throughout the duration of this study. The patients with Crohn’s disease were monitored using the Crohn’s Disease Activity Index (0 to 600 points, with 600 being the most severe disease), whilst the patients with Ulcerative Colitis were monitored using the Simple Clinical Colitis Activity Index (0 to 19, with the most severe disease being 19).
After the investigation period, the patients’ conditions improved significantly and they did not experience any adverse side effects. Three of the patients with Crohn’s disease achieved clinical remission, whilst the other observed and 151 point reduction. The patients with ulcerative colitis achieved a decrease in disease severity to 57% of baseline. However, for some patients, the treatment needed to be given at regular intervals in order to maintain the beneficial effect. Since this study was performed in 2003, further research have been carried out using T. suis to treat inflammatory bowel disease, and they have concluded their work with similar results.
N. americanus is also a species of roundworm. In this trial, 20 patients were split into either the control group or the group infected with the N. americanus larvae. Those who were infected were given 15 N. americanus larvae to consume. Although the infected patients did not show a decrease in pathology when challenged with gluten, they did show a significant decrease in compounds associated with the Th1 response. This may be due to an increase in IL-10 after challenge with gluten which is able to dampen the Th1 response,
Multiple sclerosis affects the central nervous system, often causing mobility and vision problems. In this study, four patients were treated with T. suis over six months. The end result involves the patients not experiencing any severe adverse side effects, with the helminth therapy having appeared to reduce the Th1 immune response after several months. After one month, there was actually an increase in type-1 cytokines, but then a significant decrease was recorded after two month, thereby suggesting that this was when the Th2 immune response kicked in,
Although the studies mentioned presented promising results, it is still important to note that there have been studies which do not show significant clinical improvement in patients, particularly in the treatment of allergies.
On the other hand, as mentioned before, there is a possibility of using helminth-derived compounds in the treatment of these diseases. The immuno-regulatory molecule, ES-62 from Acanthocheilonema vitae is able to cause dendritic cells to promote the type-2 immune response and weaken the type-1 immune response. Interestingly, it is also able to cause the secretion of IL-10.
Why should you care about this?
You probably would know at least one person who suffers from an allergy, and potentially someone who has an autoimmune disease.
Taking that into consideration, it comes with no surprise that these medical conditions are on the rise, especially with the increased hygienic measures that have emerged following the COVID-19 pandemic. As a matter of fact, between 5 to7% of people living in Western countries are affected by autoimmune diseases, with many of these conditions also disproportionately affecting women. Meanwhile, many of the treatments that are currently used to treat these conditions are invasive and have many unwanted side effects.
Therefore, several researchers are investigating the potential application of helminth parasites as a rather counterintuitive approach to treat these diseases. Nonetheless, there is still a lot of investigation that needs to be done into whether helminth therapy will prove itself to be a useful treatment, so keep an eye out if this interests you!
Extra resources to boost your learning appetite
If you happen to be curious, this article has summarised all the human clinical studies up to May 2020
This Youtube video talks generally about helminth parasites, which would be extremely helpful if you hope to learn more about them: https://www.youtube.com/watch?v=M7rqKQWdk8o
This TedX talk is delivered by a researcher called Dr Paul Giacomin. Having studied parasitic worms for many years, this talk involves him diving deeper into how parasitic worms could be used therapeutically: https://www.youtube.com/watch?v=sm5DcdZbnGA
Author: Ella Kline, BSc Biochemistry