Helminths and Health: Finding Purpose in Our Old Friends
A theory known as the "hygiene hypothesis" proposes that the lack of early exposure of individuals in western cultures to microbial infections results in an increase in allergies and autoimmune diseases. A recent expansion on that theory, the "old friends hypothesis," proposes that those organisms with the most influence on development of our immunity have likely existed and co-evolved with us for centuries. With records of helminth egg remains found in human feces dating as far back as 4100 BCE, it seems safe to say that these tiny parasitic worms may qualify as some of those "old friends."
Chronic infection with many soil-transmitted helminths, such as hookworms and whipworms, can lead to impaired growth, malnutrition, and anemia. Over the past decade, major global efforts have been made to eliminate soil-transmitted helminth infections through improved sanitation and administration of regular deworming treatments in endemic regions. There is no doubt that successful elimination of helminthic infections will benefit the health and well-being of those with the highest risk of chronic infection, but it appears that the human-helminth relationship is a bit more complicated than first imagined. In fact, decreases in helminth exposure due to increased sanitation and access to potable water have coincided with increases in asthma and other allergies, and with autoimmune diseases such as inflammatory bowel disease (IBD) and type I diabetes. Clearance of helminth infections via diligent deworming efforts has been shown to release suppression of the immune response, leading to both stronger anti-helminthic responses and enhanced sensitization to skin allergens such as dust mites.
By studying the culprits themselves, a growing body of research has begun to unveil a potential benefit of helminth exposure in the development of healthy, well-balanced human immune responses. Although they stimulate immune responses from infected individuals, helminths also use various mechanisms to prevent host protective immunity from fully developing. These tactics, called immune evasion, help to ensure survival of the parasite inside its human host. However, it is becoming apparent that this immune suppression has also helped to control autoimmune responses in our bodies and to prevent us from responding too strongly to certain environmental allergens. Identifying mechanisms of helminth immune evasion may help researchers harness their potential therapeutic properties of these parasites.
Allergies and Autoimmunity: Unpacking the Helminthic Knapsack
Gaining a better understanding of the worm’s side of the story may allow us to harness the beneficial properties of helminths as we simultaneously eliminate the global burden of helminth infections. Helminth infections induce a variety of host responses, including both skewing the immune response to promote worm-favorable conditions and suppressing the immune system. One way to potentially preserve the immune pressures of helminthic infections without the negative outcomes of infection is through use of some of the tools the parasites use to beneficially suppress immune responses. Current efforts are underway to investigate the potentially therapeutic properties of some of the most studied helminths. Below are some examples of helminth research that have lead to possible therapeutic breakthroughs.
Schistosoma are waterborne helminths (Fig. 1) that can cause liver, bladder, or kidney damage, but S. mansoni infection has also been linked to reduced asthma symptoms in humans, prevention of diabetes in mice and the delay of symptoms in a multiple sclerosis-type autoimmune disease mouse model. Many studies of S. mansoni have shown the important role that the eggs of this pathogen plays in modulation of immune responses during infection.
S. mansoni traverse a complicated path through the human body (Fig. 1). After adult worms deposit eggs in the blood vessels of their infected hosts, the eggs enter the intestines by penetrating the intestinal barrier, for their ultimate release into the environment. These eggs would be unable to successfully migrate to the intestinal lumen without coerced help from their host’s helpful immune responses. A crude mixture of products released from Schistosoma eggs known as soluble egg antigens (SEA) strongly pushes T cells of the host immune system to a T-helper cell 2 (Th2)* response. Directing the immune response not only protects the worm, but also protects the host from a potentially damaging Th1-mediated inflammatory response. Using a mouse model of S. mansoni infection, researchers discovered the crucial role that the Th2-produced cytokine, interleukin 4 (IL-4), plays in survival of infected mice. This and other S. mansoni-induced immune responses help to keep the host alive while the egg safely passes through its system.
Recent research has explored exactly which components within the SEA protein mixture help to skew these responses. One particular antigen, the S. mansoni glycoprotein omega-1, strongly influences host immune responses. Mice injected with only the omega-1 protein generated strong Th2 responses much like those injected with SEA.
An ongoing clinical trial is focused on exploring the protective effects of the S. mansoni enzyme, 28-kDa glutathione S-transferase (P28GST), on Crohn’s disease in humans. P28GST reduces inflammation in colitis models in rats and mice through suppression of inflammatory cytokine responses in the colons of treated animals. A separate Schistosoma species, S. haematobium, has been linked to development of bladder cancer, but this study does not rely on helminth infection at all, increasing interest in the results of this clinical trial.
Human hookworms, which include the Necator americanus and Ancylostoma duodenale nematodes, are soil-transmitted helminths (Fig. 2), the eggs of which are passed from infected individuals through their feces. Hookworm infection can cause anemia and protein deficiencies, which can lead to impaired physical and mental development in chronically infected children. However, human studies have also revealed associations between infection with N. americanus and reduced dust mite allergies in children and reduced asthma-related wheezing.
Similar to S. mansoni, a contributing factor to hookworm immune regulation is a mixture of proteins and other factors known as excretory/secretory (ES) products. Hookworm ES products induce production of the Th2 cytokine, IL-4 along with the anti-inflammatory cytokine IL-10. Researchers revealed that ES products from the canine hookworm, Ancylostoma caninum, were even able to prevent allergic responses in a mouse model of asthma due in part to induction of the Th2 cytokines IL-5 and IL-13.
Taking these findings a step further, the researchers showed that one particular protein from the mixture, AIP-2, generated the majority of the protective responses in mice, and even reduced human immune cell responses to dust mites in vitro. In a separate study using a mouse model of colitis, the authors explored the immune-suppressive capabilities of extracellular vesicles (EV), which are a fraction of ES products, from the rodent hookworm, Nippostrongylus brasiliensis. This study reported that treatment of mice with EVs induced strong IL-10 responses, and suppressed inflammatory cytokine responses.
Trials in humans, in which individuals were infected with N. americanus larvae, have had variable success. A small study of adults with the autoimmune disorder, celiac disease, showed decreased levels of the inflammatory T-cell cytokine, interferon gamma (IFNγ) in participants’ guts after infection with N. americanus. Additionally, most of those enrolled were able to withstand higher quantities of pasta challenge over time after infection. However, despite research suggesting a correlation between N. americanus and reduced asthma symptoms, clinical trials have not yet shown any positive effect of N. americanus larvae on asthma.
Discovering New Value in our "Old Friends"
Evolution of helminths with the human population has equipped many of these parasites with all of the tools necessary for successful widespread infection of our bodies without widespread death due to infections. Many of these tools function by skewing or suppressing inflammatory immune responses that may be damaging to themselves and to our own bodies if too strong. In support of the "old friends hypothesis," observations in human studies and animal models have revealed the potentially important role that helminth-driven suppression of our immune responses has played in preventing or lessening our development of allergies and autoimmune diseases. However, chronic and recurring infections in regions where these helminths are endemic often lead to detrimental health effects especially among children, thereby highlighting the importance of strong deworming campaigns and vaccine efforts in these areas.
Multiple clinical trials are in varying stages of completion investigating the therapeutic properties of not only hookworms and Schistosoma mansoni products, but also helminth products such as eggs from the soil-transmitted pig whipworm, Trichuris suis. Moreover, scientists are constantly working to discover what specific factors produced by these worms have the most protective properties, which could potentially eliminate the need for the helminth infection all together. Through these combined efforts, we can potentially see a future where disorders including inflammatory bowel diseases, multiple sclerosis, and type I diabetes may be treated and/or prevented using the tools of our old friends, while chronic helminth infections become a thing of the past.
* Th1 and Th2 cells are 2 subtypes of helper T cells of the adaptive immune system, which are induced partly in response to antigens presented to naïve T cells. Very roughly, Th1 cells are generated in response to intracellular pathogens, and produce cytokines that help infected cells to clear infections via the inflammatory response and cytotoxic T cell activity. Th2 cells are generated in response to extracellular pathogens, and produce cytokines that support antibody production to coat pathogens such as helminths. Th1 cells can inhibit Th2 cytokine production, while Th2 cells inhibit naïve T cell differentiation to Th1 cells.