Feature: The turn of the worm
15 May 2006. By Caroline Cross, a freelance writer based in Reading.
The incidence of asthma in children living in the UK has increased from less than 5 per cent in 1964 to more than 25 per cent in 1999. The reasons for this dramatic rise have remained elusive, although various possibilities have been suggested, from pollution to excessive hygiene - insufficient exposure to germs leaving our immune system on a hair trigger.
Recently, scientists have discovered another possible factor: a decline in parasitic worm infections. Studies in Ethiopia and Papua New Guinea have shown that people infected with worms tend not to suffer allergies. 1
"What we found was that people with hookworm infection were less likely to develop respiratory wheeze to house dust mites," explains Professor David Pritchard, a Wellcome Trust-funded parasite immunologist at the University of Nottingham. Scientists now want to find out what parasitic worms do to the immune response in the hope that they can learn from the parasite's experience, and turn the worm - or part of it - into an effective anti-inflammatory agent.
Regulating immune responses
During thousands of years of coevolution, parasites and humans have learned to live in uneasy harmony. A parasite must adapt to life in a host where, if detected, an immunological armoury will be targeted against it. Helminths such as hookworms and schistosomes have developed many elaborate ways to avoid and manipulate the host's immune system in order to survive.
Some have been so successful they can remain undetected in the bloodstream for several years. And schistosomes actually depend on the immune system for survival - people with defective immune systems cannot transmit schistosome eggs.
"The parasite down-regulates the immune system for its own benefit," explains Professor Rick Maizels (University of Edinburgh) - a parasite immunologist also funded by the Wellcome Trust. "But doing so has wider ramifications, because it also dampens unrelated immune responses such as allergic responses."
Using a model system, Professor Maizels has found that parasitic worms can suppress allergy by inducing a class of immune cells known as regulatory T cells. 2 Regulatory T cells have only recently come to light, but they may be important for controlling a range of inflammatory responses. They act by releasing anti-inflammatory messengers and also by interacting directly with inflammatory cells, sending them 'off' signals.
Professor Maizels believes that everyone has regulatory T cells and that these protect us from our own immune systems. "These regulatory T cells may exist naturally to prevent us suffering autoimmune diseases," he says. "We think the mechanism that is protecting us from our immune system is also protecting the parasite from our immune system." It is possible, he suggests, that once the parasite has converted T cells against itself into regulatory T cells, it also converts others - such as those that recognise allergens - into regulatory T cells.
And it may not be just parasitic worms that exploit these cellular safety mechanisms. According to Professor Maizels, harmless bacteria living in our guts and slow-growing mycobacteria may show similar traits. The race is now on to isolate the molecules that elicit these beneficial responses and harness them to treat inflammatory disorders.
There may also be other cellular mechanisms involved. Dr Padraic Fallon and colleagues at Trinity College Dublin have shown that schistosomes also prevent experimental asthma, but he believes there is more to it than regulatory T cells. "Although regulatory T cells are relevant, it is too convenient to expect that worms would evolve to be dependent on a single cell type to suppress allergic responses."
The Dublin team has shown that schistosomes have other tricks to play. Schistosome eggs protect themselves from the host's immune system when inflammatory cells are recruited, forming a mass of cells called a granuloma around the egg. The researchers found that schistosomes employ a novel tool to keep the immune system at bay. They knew already that soluble messenger proteins (chemokines) were involved in granuloma formation; might the parasite be interfering with this signalling?
"Viruses produce chemokine-binding proteins to suppress inflammation, so we looked for chemokine-binding proteins in schistosomes," says Dr Fallon. What they found was a protein they called smCKBP - the first non-viral chemokine-binding protein to be characterised. 3 It binds to IL-8, which normally attracts inflammatory cells called neutrophils to sites of inflammation. Schistosome egg granulomata lack neutrophils, suggesting that it is likely that smCKBP secreted by the egg blocks neutrophil recruitment. "It seems to have evolved to work around the schistosome egg to suppress local inflammation and protect the eggs, but not to suppress the immune response generally," explains Dr Fallon.
The team has found that the protein works in some model systems of inflammation but not others - for example, it is effective against models of psoriasis but not arthritis. "This makes the point that it might have specific applications. It is not a broad-spectrum anti-inflammatory agent," notes Dr Fallon. But he hopes it will be developed to treat conditions such as psoriasis.
Worm biotherapy
Although many scientists are keen to understand the mechanisms and molecules employed by worms, others defer to the worm's superior understanding of the immune system. The worm's potential as a 'biotherapy' is currently being tested in clinical trials. In the USA, scientists are using pig whipworm eggs to treat people with ulcerative colitis. 4 And in the UK, Professor David Pritchard and Professor John Britton are testing the human hookworm as a treatment for hay fever, and potentially asthma, in a trial funded by the Wellcome Trust.
Professor Pritchard believes the human hookworm is a good candidate for treating asthma and allergies. "We know a lot about hookworms. We've been looking at them for 20 years," he says. The hookworm trial has been set up with a carefully selected dose of parasites that won't cause lung inflammation, but should reduce allergic symptoms.
Although results of the trial will not be known until October 2006, it will if successful be extended to people with asthma. And one of the first things Professor Pritchard will be looking for is changes in the regulatory T-cell population. "Worms may have the secret of how to stimulate regulatory T cells," he says.
But in the 21st century, is it realistic to expect people to agree to a wormy medicine? Professor Pritchard doesn't see a problem: "People are used to kids and dogs getting worms. There doesn't seem to be much stigma attached to it." However, others think the logistics of producing a standardised 'biotherapy' that could be applied by non-specialists would make it impractical for use on a large scale. Progress may depend on identification of the underlying mechanisms and active molecules. But perhaps the parasites will have the last word. After all, when it comes to manipulating immune responses, they have thousands of years of experience; immunologists have only a few decades.
Image: Mouthparts of the hookworm A. duodenale; image courtesy of MEDDIA, Royal Tropical Institute, Amsterdam/BE Matthews.
References
1. Scrivener S et al. Independent effects of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: a nested case-control study. Lancet 2001;358(9292):1493-9.
2. Wilson MS et al. Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J Exp Med 2005;202(9):1199-212.
3. Smith P et al. Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity. J Exp Med 2005;202(10):1319-25.
4. Summers RW et al. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 2005;128(4):825-32.