Parasites to the Rescue

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Leonie Hussaarts explores how parasitic worms can help protect us against allergy and autoimmune disease

 

In an attempt to cure his chronic bowel inflammation, a 34-year-old Californian infected himself with the parasitic worm Trichuris trichiura. He flew to Thailand, where he ingested worm eggs from the stool of an 11-year-old girl. He got better.

 

Worms-2Most of us think of parasites as bad guys that feed off our bodies at our expense. Not surprisingly, considering that the malaria parasite kills a child every minute. The thought of another class of parasites, the parasitic worm, also evokes feelings of disgust. But is this justified? While autoimmune diseases and allergies are a major public health problem in the Western world, such diseases remain rarities in developing countries where parasite infections prevail. A possible explanation for this phenomenon lies in the hygiene hypothesis, which states that improved hygiene has rendered our immune system hypersensitive to innocent stimuli, such as the house dust mite, pollen, and even our own body.

Parasitic worms, also called helminths, are a major theme in the hygiene hypothesis. They come in many different forms and together infect around two billion people worldwide, mostly in Africa, Southeast Asia and South America. They are transmitted through soil or water, and can live in different organs, depending on the species. Strikingly, a number of studies have demonstrated a negative association between helminth infections and inflammatory diseases, such as allergy and autoimmune disease.

Do these parasites protect us against such diseases? Let’s try to answer this question at the hand of some basic immunology. Inflammatory responses (that is, responses of white blood cells following encounter of dangerous invaders) are initiated by the sensors of our immune system: the so-called “dendritic cells”. These dendritic cells patrol our body at the interfaces with the outside world, such as the lungs, the intestine, or the skin.

When dendritic cells come across dangerous invaders, also called pathogens, they digest the pathogen and present pieces of it to other immune cells, called T cells, which then become activated to specifically eliminate that particular invader. T cells produce molecules that either kill the pathogen or that direct the immune response. T cells that direct the immune response help to attract many other immune cells and are therefore called T helper cells. Depending on the type of pathogen, various T helper responses can be initiated. Most common are T helper 1 cells, which protect us from viruses and bacteria, and T helper 2 cells, which fight parasite infections. Inflammatory responses can also be harmful if they are not properly regulated. Therefore, negative feedback is provided by a regulatory network which keeps the inflammation in check.

During their patrol, dendritic cells also come across a lot of substances which are harmless, such as many different foods, pollen, spores, the house dust mite, and molecules of our own body. Upon encountering these substances, dendritic cells of healthy individuals immediately activate a regulatory network that suppresses the inflammatory response, thereby inducing tolerance. In allergic diseases, this regulatory network is not activated and dendritic cells turn on T helper 2 cells instead, which marks the start of the immune response to the harmless molecule. In autoimmune disease, our white blood cells are even less well-behaved, and start to attack the body itself. It is thought that the failure to induce a regulatory network may explain why our immune system goes bad. The hygiene hypothesis states that his may be a consequence of lack of exposure to infections early in life: our immune system may simply never have learned how to induce regulatory responses.

Perhaps surprisingly, helminths are the infectious agents that activate the strongest T helper 2 responses in nature, but they also protect against allergies, which too are characterized by T helper 2 induction. Helminths have coevolved with humans and, as a consequence, they have learned to exploit our immune system. In order to safeguard their survival in the human host, the parasitic worms apply a brake to T helper 2 responses and induce a strong regulatory network. Over the last decade, it has become evident that the regulatory network induced by parasites extends its influence and not only protects against parasite expulsion, but also against allergy.

Worms-1In autoimmune disease, it gets slightly more complicated. Even though the immunological basis of different autoimmune diseases varies, helminths protect against many of them, including multiple sclerosis, inflammatory bowel disease and diabetes. In multiple sclerosis, where white blood cells attack brain cells, it is thought that regulatory networks induced by helminths are responsible for disease remission. In autoimmune diabetes and inflammatory bowel disease, uncontrolled T cell responses cause disease. Here, both parasite-induced T helper 2 responses and regulatory responses seem to ameliorate the pathological effects of uncontrolled T cell responses.

If these parasites protect against so many diseases, then why don’t we give them to patients therapeutically? In areas where parasite infections are endemic, many individuals chronically infected with helminths do not experience any infection-related problems. However, complications such as organ failure can occur. Especially in the Western world, where infection rate is low and people’s immune systems are poorly educated, it would thus be too dangerous to treat patients with helminths capable of infecting humans. Studies on parasite therapy are therefore focusing on worms which infect other mammals.

An example is Trichuris suis ova (TSO) therapy, where patients are treated with the larvae of the Trichuris suis worm, which normally infects pigs’ intestines. In humans, the larvae do not mature into adults, and therefore the infection cannot become chronic. Clinical trials are promising, especially for inflammatory bowel disease, as TSO treatment has shown to promote disease remission. However, patients with allergic rhinitis (allergic inflammation of the nasal airways) could not but cured by TSO therapy, and suffered from side-effects like diarrhea.

From a medicinal perspective, it would therefore be interesting to understand how these parasites operate at a molecular level. If we can understand how they induce T helper 2 and regulatory responses, it would perhaps be possible to design drugs that mimic the parasites’ behavior. Thus far, it has been established that certain parasite molecules manipulate dendritic cells which then preferentially induce T helper 2 and regulatory responses. Studying how these molecules manipulate dendritic cells is a hot topic in the field of immunology, and the outcome of these studies may be the starting point of curing many of our modern diseases.

Leonie Hussaarts (‘09) is obtaining her PhD studying helminths and other things small and squiggly at the Department of Parasitology of the Leiden University Medical Center.

Literature

  1. Labyrint, “De Darmen: Poep als medicijn”, 19 October 2011

  2. Maizels et al., Regulation of pathogenesis and immunity in helminth infections, J Exp Med, 2009

  3. Wolff et al., Helminthic therapy: improving mucosal barrier function, Trends parasitol, 2012

  4. Maizels and Yazdanbakhsh, Immune regulation by helminth parasites: cellular and molecular mechanisms, Nat Rev Immunol., 2003

 

Table: T cell responses in health and disease

 

T cell subset

The good guy:
Protects against

The bad guy:
A major player in

T helper 1

Bacteria and viruses

Autoimmune disease

T helper 2

Helminth infection

Allergy, asthma

T helper 17

Bacteria and yeast

Autoimmune disease