• Triple Helix

Parasitic Worms: Medicine’s Unlikely Ally?

Written by El Hebert '24

Edited by Lizzy Zhang '24

This hookworm is not your friend… or is it? DPDx Image Library, 2004, hosted on Wikimedia Commons.


When most people first see an Ascaris worm, preserved in a specimen jar or microscope slide, their immediate reaction is a grimace of horror. At about palm-length, often longer, Ascaris looks clammy, pale, and capable of serious squirming. But unlike the familiar earthworms of the soil, this creature makes its home inside us. In fact, Ascaris carries out its squirming in the intestines of more than 807 million humans worldwide. [1]


Dreadful as the thought may seem to us now, though, parasitic worms like Ascaris were once so widespread as to be a simple fact of life. And they’ve been with us forever: Archaeologists have found their eggs in ancient human droppings and the intestines of mummified individuals [2]. Some, like the tapeworm, we even inherited from our primate ancestors [3]. In fact, nearly every large and complicated animal has its own contingent of smaller, simpler worms that evolved to live happily inside them. These organisms, known as helminths, form a booming ecological industry, a check and balance for the whole network of nature — but we humans decided to exempt ourselves.


As sanitation and medication improved worldwide through the 20th century, our helminths, which often spread through soiled food, lost a good chunk of their foothold. In wealthier nations, most of us now lead worm-free lives, and we like it that way. Helminths, after all, can cause disease: abdominal pain, intestinal obstruction, malnutrition as they leech off our resources. None of that sounds pleasant. However, in shrugging off our evolutionary partner - even an unwilling partner - we may have opened the door to a different kind of trouble.


Day and night, our immune systems work faithfully to protect our bodies from parasitic freeloaders — not just helminths, but bacteria, viruses, fungi, and more. The human immune system commands the body’s heaviest defensive weapons: toxic chemicals, cell armies, and control over fever and inflammation. A well-timed and well-regulated immune response can and has saved your life, but a misfire could end it. In severe COVID-19 disease, it’s a runaway inflammatory response, an overreaction by the well-meaning body, that kills. [4]


For many of us, in fact, a runaway immune response is not just a worst case-scenario but a daily issue. In allergic reactions - estimated to affect 30-40% of the world’s population [5] - the immune system kicks into full destructive force over a harmless molecule in the environment, like a pollen protein or an antibiotic drug. The effects range from uncomfortable to deadly. Other common diseases of uncalled-for inflammation include ulcerative colitis, Crohn’s disease, and asthma.


In the 1970s, population-level studies of these ailments began to turn up some intriguing patterns. It seemed, ironically, that better hygiene correlated with more pervasive allergic and inflammatory diseases. Children who grow up with livestock or older siblings, or in lower-income nations, are less likely to show allergic and asthmatic symptoms. Some studies even suggest that sleeping on a dusty mattress in early life can protect against respiratory sensitivity in later childhood! Thus, the “hygiene hypothesis” was born: perhaps we need exposure to microbes and grime so our immune systems can learn when to calm down [6].


In this dance of friend and foe, helminths may have a special role to play. As it turns out, our immune response to helminths involves many of the same mechanisms that cause allergic symptoms. Humans actually tend to come with built-in allergies to helminths and their body fluid [7]. So why, instead of allergy and inflammation, do helminth infections cause intestinal symptoms - or sometimes no symptoms at all?


Immunologists studying the interplay between host and parasite agree that the worms set up a kind of communication with the host’s immune system. After so much time spent evolving alongside us, they know how to calm our defenses and quiet our cells’ chemical alarms. By tricking our bodies, they can fly under the radar and survive in an uneasy peace. And current research suggests that such a placated immune system becomes less inclined to overreact to something harmless, like peanuts or pollen [8].


For example, in a 2003 study of more than 2000 school-age children in Ecuador, children infected with helminths (including our old friend Ascaris) were significantly less likely to test positive for common skin allergies [9].


In the lab, mice can be sensitized to egg protein, leading to the development of allergies - the same way many people develop new allergies throughout their lives. However, when biologists try this trick on mice with helminth infections, the new allergies are suppressed. This effect is so reliable that researchers can use it to study the entire helminth-host interaction [8].


And so a bizarre yet promising question follows: can we bring these benefits to real patients? Could we harness one disease to treat another?


Some helminth researchers, eager to bring their findings to the patients of the world, have already launched clinical trials of helminth therapies. In these tests, informed volunteers consume just enough dormant worm eggs to cause a mild, transient infection, usually symptom-free. Nearly all trials ensure safety by using the pig whipworm, Trichuris suis, which is not adapted to survive long-term inside a human. These trials prove that helminth therapy can be applied safely in a clinical setting, but whether it’s effective is another story.


Some small pilot studies produced significant disease improvements, like a series of ulcerative colitis trials carried out by Dr. Robert W. Summers and his team between 2003 and 2005 [10]. Other studies, including those with larger sample sizes, fail to produce such benefits. In 2013, two larger-scale trials investigating helminth therapy for Crohn’s disease were shut down due to lack of efficacy. These trials, which involved 250 and 240 patients, respectively, did not result in symptom improvement. In allergy, too, the positive effects seen from lab mice seem not to transfer to humans.


If helminths reliably help those mice, and may even protect humans at a population scale, why can’t we make them work in the pharmacy? One possibility stems from the timeline of disease and treatment itself. In the “wild,” and in most animal studies, a human or animal picks up helminths before they encounter an allergen or other trigger for inflammation; in clinical trials, people volunteer for helminth treatment because they’re already suffering from an immune disorder. Perhaps helminths can protect, but not cure.


Another possible factor is the severity of helminth infection: after all, researchers treat humans with far fewer worms, for far shorter periods, than they do mice! And then there’s the complexity of the immune system and its parasite defenses. This field is young, and we don’t know enough yet to predict all its intricacies [11].


But researchers haven’t given up. Immunologists, zoologists, chemists, doctors and more continue to probe the weird little world of helminths and their hosts, searching for better answers and more reliable solutions. One promising path, for example, forgoes the worm entirely in favor of its chemical messages, the molecules used to communicate with our immune systems. If these compounds could be isolated and packaged into a pill, prescribers could directly target the problem without the unsavory, parasitic middleman [12]. At the very least, we’ll learn more about what makes our bodies tick, and how closely intertwined we are, in sickness and health, to even the smallest of our fellow Earthlings.


Our bodies are not only our own; they’re ecosystems, in constant communication with other life forms around and inside us. And though we’d like to think we have control over what’s going on in that system - though many of us would rather bid farewell to Ascaris and its ilk for good - that’s not always the case. Inflammatory disease shows us how our defensiveness can quite literally kill us. So perhaps the path forward is to embrace this messy balance, to keep untangling the causes and complications behind these studies, and, eventually, to make peace with our worms.

 

References


[1] Center for Disease Control. Parasites: Ascariasis [Online]. Last updated 2020 [cited 16 Oct 2022]. Available from: https://www.cdc.gov/parasites/ascariasis/index.html.


[2] Gonçalves ML, Araújo A, Ferreira LF. Human intestinal parasites in the past: new findings and a review. Memórias do Instituto Oswaldo Cruz. 2003 [cited 16 Oct 2022];98:103-18. DOI: 10.1590/s0074-02762003000900016.


[3] Leles D, Gardner SL, Reinhard K, Iñiguez A, Araujo A. Are Ascaris lumbricoides and Ascaris suum a single species? Parasites & vectors. 2012 Dec [cited 16 Oct 2022];5(1):1-7. DOI: 10.1186/1756-3305-5-42.


[4] Zheng M, Karki R, Williams EP, Yang D, Fitzpatrick E, Vogel P, Jonsson CB, Kanneganti TD. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nature immunology. 2021 Jul [cited 16 Oct 2022];22(7):829-38. DOI: 10.1038/s41590-021-00937-x


[5] Pawankar R, Canonica GW, Holgate ST, Lockey RF. White Book on Allergy 2011-2012 Executive Summary. World Allergy Organization. 2013 [cited 16 Oct 2022]. Available from: https://www.worldallergy.org/wao-white-book-on-allergy.


[6] Liu AH, Murphy JR. Hygiene hypothesis: fact or fiction?. Journal of Allergy and Clinical Immunology. 2003 Mar 1 [cited 16 Oct 2022];111(3):471-8. DOI: 10.1067/mai.2003.172.


[7] Sereda MJ, Hartmann S, Lucius R. Helminths and allergy: the example of tropomyosin. Trends in parasitology. 2008 Jun 1 [cited 16 Oct 2022];;24(6):272-8. DOI: 10.1016/j.pt.2008.03.006.


[8] Cooper PJ, Chico ME, Rodrigues LC, Ordonez M, Strachan D, Griffin GE, Nutman TB. Reduced risk of atopy among school-age children infected with geohelminth parasites in a rural area of the tropics. Journal of Allergy and Clinical Immunology. 2003 May 1 [cited 16 Oct 2022];111(5):995-1000. DOI: 10.1067/mai.2003.1348.


[9] Helmby H. Helminths and our immune system: friend or foe?. Parasitology international. 2009 Jun 1 [cited 16 Oct 2022];58(2):121-7. DOI: 10.1016/j.parint.2009.02.001.


[10] Summers RW, Elliott DE, Urban JF, Thompson RO, Weinstock J. Trichuris suis therapy in Crohn’s disease. Gut. 2005 Jan 1 [cited 16 Oct 2022];54(1):87-90. DOI: 10.1136/gut.2004.041749.



[11] Helmby H. Human helminth therapy to treat inflammatory disorders-where do we stand?. BMC immunology. 2015 Dec [cited 16 Oct 2022];16(1):1-5. DOI: 10.1186/s12865-015-0074-3.


[12] Harnett W. Secretory products of helminth parasites as immunomodulators. Molecular and biochemical parasitology. 2014 Jul 1 [cited 16 Oct 2022];195(2):130-6. DOI: 10.1016/j.molbiopara.2014.03.007.


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