Fighting Allergies by Mimicking Parasitic Worms
As blossoming spring trees spew pollen, many allergy sufferers would be grateful for a more effective way to alleviate their itchy misery. How about swallowing a batch of pig whipworm eggs, or deliberately infecting oneself with the fecal-dwelling hookworm? Yucky as these options sound, mounting evidence in both humans and animals suggests that infection with these parasitic worms seems to protect against a number of inflammatory diseases, including asthma and allergy, multiple sclerosis, Crohn’s disease, and type 1 diabetes.
Because parasitic infection is unappealing to even the most severe allergy sufferer, some scientists hope to decipher how these organisms control the immune systems of their human hosts and to develop new therapies that replicate the parasites’ beneficial effect. “We can treat people with worms, or can we figure out how worms protect, and discover a new way to treat allergies by mimicking what worms do,” says Ed Mitre, a physician and scientist at the Uniformed Services University in Bethesda, MD. “My general feeling is that we should be trying to induce the types of immune responses we see in chronic worm infections.”
A number of epidemiological studies have shown that people infected with parasitic worms suffer less from allergies and other immune diseases, and research in animal models designed to mimic these diseases supports these findings. The rise in allergies and other ailments in rich countries over the last few decades has been matched by a decrease in parasitic worm infection, among other factors. “When you have organisms that have lived together for hundreds of thousands of years, they become mutualistic rather than combative,” says Joel Weinstock, a physician and scientist at Tufts University, in Boston. “Possibly we became dependent on helminths [parasitic worms] and made ourselves vulnerable to immunologic diseases.”
The mechanism behind the organisms’ protective power is not yet clear. Infection with parasitic worms induces an allergic response called TH2, the same one triggered by allergens, raising levels of an antibody called immunoglobulin E (IgE). Binding of thatantibody to specific immune cells in the blood signals the cells to dump their contents, including histamines, into the bloodstream, triggering the typical allergy symptoms. However, “people with parasite infections have lots of IgE in their serum and lots of the cells that cause allergies, but they don’t have allergies,” says Lisa Ganley-Leal, an immunologist at Boston University.
Ganley-Leal thinks she has discovered one of the mechanisms behind this apparent paradox. Studying the parasitic flatworm schistosoma in test tubes, her team found that the worms produce an enzyme that chops up free versions of the IgE receptor in a unique way. These fragments then bind to the IgE antibody, preventing it from binding to receptors on the surface of immune cells and thus stopping the cells from releasing troublesome histamines.
The researchers found that people with parasitic infections have these unique protein fragments in their bloodstreams, while unaffected people have few or none. “We think the worm modifies this protein as an immune invasion tactic,” says Ganley-Leal, who presented the research at a conference in Boston earlier this week. “By blocking IgE’s ability to bind to cells, we think the worm is protecting itself, and that also seems to protect the host.” Her team is now producing this modified protein, which they plan to test in mice that have the human version of IgE receptors. Ganley-Leal has formed a company called Epsilon Therapeutics to commercialize the technology.
This mechanism is just one possible explanation for parasites’ protective effects. Because parasitic worms coevolved with us for the vast majority of human history (even mummies have them), they likely evolved ways to turn down the immune system just enough to permit their survival without severely harming their hosts. “I think the consensus, if there is one, is that chronic worm infections induce an immunoregulatory response in the body,” says Mitre. “Exactly how that immunoregulatory milieu is set up remains unknown.”
In fact, the IgE system may have evolved as a way to keep parasites in check. As our environment became cleaner and infection more rare, at least in rich countries, pollen and food allergies may have developed as collateral damage. By studying these organisms, “we may be getting at the basic pathophysiology of these diseases,” says Weinstock. “In terms of drug discovery, this is a major unexplored area. But it’s hard to know if a single component of worms will ever work as well as worms themselves.”
At this point, worm-based treatments are further along in clinical development than worm-inspired ones. A study found that infecting inflammatory bowel disease sufferers with pig whipworms helped alleviate symptoms, although a similar study with allergic rhinitis sufferers showed no effect. (This may be due to the choice of worm–pig whipworms live in the gut and thus may not exert a strong enough effect on the respiratory system.) A handful of other clinical trials are currently under way.
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