SUBSCRIBE HomeArchiveDecember 2021Features Return of the Worms Immunologists and parasitologists are working to revive the idea that helminths, and more specifically the molecules they secrete, could help treat allergies and autoimmune disease. Catherine Offord Dec 1, 2021 55 ABOVE: Illustration of a tapeworm infestation in a human intestine © ISTOCK.COM, CHRISTOPH BURGSTEDT I n the middle of 2020, Alex Loukas deliberately infected himself with intestinal worms. The procedure was pretty straightforward: he used a Band-Aid to press a few larvae of the New World hookworm (Necator americanus) gently onto his forearm, and waited for the microscopic critters to burrow on in. Although it wasn’t painful, exactly, he describes a tingly feeling like “little tiny electric shocks as these guys go through your skin,” he says. “It’s intensely itchy for a number of days and then that resolves.” Some people who undergo this process experience stomach discomfort when the worms arrive in the gut, where they will grow up to 1 cm long, but many “will then never have any other clue that they’re infected.” There were several reasons that Loukas wanted the parasitic worms, or helminths, on board. For one thing, his research at James Cook University in Australia focuses on multiple aspects of N. americanus biology, and as obligate human parasites, these intestinal worms just don’t grow very well outside of people. Rearing a few in his own gut and then collecting eggs via a bathroom visit would be a lot simpler than trying to maintain a population in the lab, Loukas explains. (Judging by how many eggs he’s currently shedding—he estimates it’s around 20,000 per day—his worms seem to be doing just fine.) Loukas has also, in the course of his research, developed the view that infection with N. americanus and other intestinal helminths, which together are thought to inhabit at least 2 billion people worldwide, isn’t always harmful. In fact, he argues, work by his group and others indicates that there could be some unique benefits to controlled, low-level infection with certain worm species, particularly for combating so-called Western diseases, including allergies, autoimmune disorders, and various other inflammation-related conditions. As an advocate for exploring helminth infection as a potential therapy against such conditions, Loukas realized he had to give it a go. “I’m sitting there telling the world how great this is,” he recalls thinking. “I should probably experience it for myself.” People still believe that there are good immunological reasons for continuing to pursue this. —William Harnett, University of Strathclyde Often referred to as immunoregulators, helminths secrete and excrete vast quantities of proteins and other molecules that influence the activity of the host immune system. It’s a strategy born of necessity for a large, multicellular parasite that typically persists months or years in a single gut and, unlike a bacterium or virus, can’t out-multiply its host’s defenses, says Rick Maizels, an immunologist at the University of Glasgow and Loukas’s former postdoc adviser. Helminths have been coevolving with humans for as long as humans have been around. Until a century or so ago, when improved hygiene and healthcare began to wipe out worm infections in industrialized countries around the world, “the whole human population would have had these parasites for most of their life,” Maizels says. “They’ve had all the time in the world to adapt and to learn how best to live in the environment.” This intimate biological relationship forms the basis for the argument made by Maizels and others that helminths play a crucial role in keeping harmful immune responses in check—and that their loss in certain modern societies might account for some of the observed increases in autoimmune and inflammatory conditions. It’s a controversial theory that some scientists have taken issue with. Parasitic diseases expert Peter Hotez of Baylor College of Medicine and colleagues have questioned whether the observed associations are causal, noting that research has found that many helminths can exacerbate and may even promote inflammatory conditions; a few years ago, Hotez referred to worm therapy as belonging in the category of “pseudoscience cult therapies.” But although Loukas, Maizels, and others in the field agree that some helminth infections can be dangerous and require treatment, they posit that the manipulation of the immune system by more-benign species may in some cases be able to rein in immune responses that are potentially harmful to the host. Previous attempts to convert this line of thinking into therapies for immune-related conditions have had mixed success. Despite a promising start in the early 2000s, subsequent clinical trials of helminth infection as a treatment for conditions including Crohn’s disease, celiac disease, and asthma generally produced unimpressive results. Unfazed, proponents of the approach are now coming at the problem from a different angle, one that places stronger emphasis on understanding the mechanisms underlying host/helminth interactions, and views both the worm and the individual compounds it secretes as potential therapeutics. “There’s been disappointment over the results of the trials,” says William Harnett, an immunologist of the University of Strathclyde in Scotland who is named as an inventor on patents covering the therapeutic use of some worm-derived molecules. But “I think people still believe that there are good immunological reasons for continuing to pursue this.” See “Opening a Can of Worms” Keeping the immune system in check P’ng Loke was a postdoc at the University of California, San Francisco, working on mouse models of helminth infection when he met the man who’d become his first human subject. It was 2006, and the 35-year-old man, diagnosed with ulcerative colitis a couple of years earlier, had taken an unusual approach to tackling his debilitating symptoms: having heard stories of helminths’ possible anti-inflammatory effects, he’d traveled to Thailand and gotten his hands on more than a thousand whipworm (Trichuris trichiura) eggs, which he’d swallowed. This behavior isn’t unheard of among people with severe inflammatory diseases, Loukas says, and there’s a troubling black market for helminth eggs in many countries and online. Remarkably, the man’s ulcerative colitis seemed to be in remission. So Loke began studying the man’s physiology, using colonoscopy images and intestinal biopsies, some of which had been collected prior to the egg-swallowing and others afterward. “We followed him for a few years and really characterized what was happening in his gut,” says Loke, now with the National Institute of Allergy and Infectious Diseases in Maryland. GUT RESIDENT: An adult male Heligmosomoides polygyrus, an intestinal parasite of rodents JANICE MURRAY, MAIZELS LABORATORY The researchers found that the man’s colon, which had been inflamed prior to his worm infection in 2004, showed less damage in 2005, and there had been a reduction in the number of inflammatory cells known as neutrophils. This switch occurred more than once: after experiencing worsening symptoms in parallel with a decline in helminth eggs in his stool in 2008, the man reinfected himself, this time with 2,000 eggs, and his colon showed the same calming of symptoms following that infection too, Loke says. From additional analyses, the team also found that while his gut had been full of T helper cells producing the inflammatory cytokine IL-17 just prior to his swallowing more worm eggs in 2008, it now contained T helper cells producing IL-22, a cytokine involved in repairing the gut wall. “It looked like worms were restoring the mucosal barrier.” The value of such one-off studies is limited from a therapeutics point of view. “They are just case reports,” says Loke. “You don’t really know how broadly applicable it is.” But they do help researchers piece together the mechanisms by which helminths modify human biology, as do complementary studies on animals infected with worms. Maizels has also been digging into these mechanisms over the last few decades, and has documented myriad ways in which helminths manipulate and evade host immunity. (See illustration on page 30.) In his view, intestinal worms essentially “decide that they’re a transplant,” he says. “They walk in and assimilate themselves as if they were a normal part of the body.” Several of the mechanisms Maizels has studied operate via regulatory T cells, or Tregs for short—specialized immune cells that typically dampen immune responses. Human studies, for example, have found higher levels of Tregs in the blood of people infected with N. americanus or the large roundworm Ascaris lumbricoides compared with worm-free controls. Maizels and others have also reported that helminth infection is associated with increased production of immunoglobulin G4 (IgG4), an antibody released by B cells that is associated with anti-inflammatory pathways. Levels of IgG4 typically fall in people whose helminth infections are eliminated with deworming drugs. These kinds of studies help provide support for new clinical trials. Last year, scientists in the UK reported findings from a randomized controlled trial of N. americanus infection as a therapy for relapsing multiple sclerosis. As predicted, worm infection boosted Treg levels in people’s blood, the researchers reported. There were also fewer relapses among hookworm-infected people than in the placebo group, though this finding wasn’t statistically significant. Loukas’s group, meanwhile, has been studying host-helminth interactions in type 2 diabetes, another condition associated with elevated inflammation. Earlier this year, he and his colleagues published data from a study of mice fed fatty or sugary diets: animals infected with the nematode Nippostrongylus brasiliensis had higher levels of anti-inflammatory cytokines such as IL-4 than uninfected controls and were protected from diabetes-like pathology. Loukas and colleagues are now running a randomized controlled trial to assess safety and tolerability of hookworm infection in people who are obese and show insulin resistance or other symptoms of metabolic syndrome. (The team is using hot sauce to simulate the tingly feeling of burrowing larvae on the arms of people in the placebo group.) Despite this progress, results from the latest handful of clinical trials haven’t been hugely encouraging. A small randomized controlled trial of celiac patients published earlier this year by Loukas and colleagues, for example, failed to find a positive effect of hookworm infection on gluten tolerance when people consumed moderate amounts of the protein, although when given questionnaires about their experience, some helminth-positive people reported higher well-being and quality of life. (Loukas tells The Scientist that researchers had trouble establishing stable infections in some participants, perhaps because worms fared badly on the trip from Australia to the New Zealand trial site.) An earlier, smaller trial led by the same group had suggested a beneficial effect of worm infection on gluten tolerance, but it wasn’t placebo-controlled. “I think that’s the part that’s really difficult,” Loke says of the placebo effect in helminth therapy studies. “Before we started to do trials, I never really appreciated how strong the placebo effect can be.” Moreover, he adds, the complexity of worm-host interactions makes it hard to know whether a negative trial result means a helminth therapy is completely ineffective, or just that the treatment only helps specific subpopulations of patients. One way to resolve this puzzle could be to learn more about variation in immune system responses to helminths, something that Loke is working on now. Another may be to take the worm, a multicellular animal with its own lifecycle and behavior, out of the equation. Potential therapies in worm secretions Around a decade ago, Loukas set out to determine what exactly the dog hookworm Ancylostoma caninum pumps into the gut of its host. Using some of the best available protein identification techniques to analyze secretions and excretions from A. caninum worms in culture, Loukas and colleagues identified more than 100 different proteins. When they revisited the same question a couple of years ago using more-sensitive technologies, they found 315 different proteins; Loukas suspects newer methods would identify even more. Deciphering how these proteins interact with the mammalian immune system is a mammoth task, and some research groups have decided to focus on characterizing the form and function of specific peptides that seem likely to have therapeutic properties. Harnett has worked particularly on ES-62, a glycoprotein secreted by the rat parasite Acanthocheilonema viteae, which typically inhabits tissue deep under the skin rather than the gut. The immunomodulatory part of this protein—“the business end,” as Harnett calls it—consists of several phosphorylcholine groups that the team has shown influence mammalian immune cells in vitro and in mice. “At the molecular biochemical level, it’s interfering with the immune system cells’ ability to produce inflammatory responses,” he explains. This happens in “quite a range of cells,” including macrophages, dendritic cells, and mast cells as well as B cells and T cells, and at least in some cases depends on toll-like receptor 4 (TLR4), a protein on these cells’ surfaces. The team has been testing the molecule in animal models of disease; last year, for example, the group reported that ES-62 extended “health- and lifespan” in some mice fed a high-calorie diet throughout their lives. “We got some really interesting data from that,” Harnett says, adding that although both male and female mice showed better health with worm treatment, only male mice lived longer, for reasons the team doesn’t fully understand. While the results haven’t all been good—a couple of years ago the researchers reported ES-62’s failure to protect mice against type 1 diabetes, multiple sclerosis, and inflammatory bowel disease (IBD)—Harnett says the team is now involved in developing small-molecule drugs that could mimic ES-62 and serve as potential therapeutics. The University of Strathclyde recently secured a licensing agreement with the US-based company Vimelea Therapeutics (“vimelea” means “parasite” in Swahili), which will aim to develop drug candidates for cutaneous lupus, he says. “That’s just taken off in the last few months.” GUT GUESTS Scientists are only just beginning to understand how parasitic helminth worms inhabiting the mammalian intestine and other tissues manipulate their hosts. In at least some cases, helminths may help dampen inflammation, and researchers are pursuing new therapies for autoimmune and inflammatory conditions that tap into worm-mediated signaling. A selection of the species—some of which infect animals other than humans—and proposed mechanisms, based mainly on in vitro and animal studies, are illustrated below. © NICOLLE FULLER WORM PRODUCTS Helminths release hundreds of different molecules, some of which are packaged into extracellular vesicles that may be taken up by host cells. ANTIBODY RESPONSES Helminth infection may trigger B cells to produce IgG4, an antibody suggested to be involved in anti-inflammatory responses. MICROBIAL INTERACTIONS Several worm species are associated with altered microbiome compositions. MOLECULAR FOUNDRY Some of the molecules secreted by N. americanus have shown promise in mouse models of inflammatory bowel disease. BLOCKING INFLAMMATION A protein called ES-62, released by Acanthocheilonema viteae, may inhibit the release of inflammatory cytokines such as IL-12 from dendritic cells and T helper cells. PROMOTING CALM ES-62 also induces regulatory B cells to produce IL-10, reining in inflammatory pathways. REGULATORY T CELLS Hp-TGM, a molecule secreted by Heligmosomoides polygyrus, mimics mammalian TGF-β and can upregulate regulatory T cells, which dampen inflammation. ALLERGY ASSOCIATIONS A protein produced by H. polygyrus called Hp-ARI may neutralize cytokines such as IL-33 that are associated with allergy-related inflammation. GUT BARRIER Infection with Trichuris trichiura may stimulate CD4+ T cells to produce cytokines such as IL-22 associated with mucin production and gut wall protection. See full infographic: WEB | PDF Other groups have zeroed in on compounds secreted by Heligmosomoides polygyrus bakeri, an intestinal parasite of rodents. One international team recently found that mashed-up H. polygyrus larvae dampened the activity of various immune cell types in vitro. Using a series of assays including heat inactivation and chromatography to identify active ingredients in the mixture, researchers picked out the enzyme glutamate dehydrogenase as one protein that could be responsible for some of the worm juice’s effects. Intranasal treatment with this molecule suppressed allergic airway inflammation in mice, the researchers report in their paper, and could perhaps be used as the basis for an anti-inflammatory therapeutic for asthma or related conditions in the future. Additional H. polygyrus peptides include Hp-ARI, which blocks certain inflammatory pathways by neutralizing the cytokine IL-33, and Hp-TGM, which mimics the mammalian protein TGF-β and which Maizels and colleagues found to activate a pathway that upregulates Tregs. “That’s turned into a really fascinating story,” Maizels says, noting that the protein contains several mystery structures in addition to the TGF-β–mimicking part that the team thinks might be involved in determining where Hp-TGM goes. “So it has both an address and a message, if you like.” The therapeutic potential of Hp-TGM is still unclear, however. Maizels and colleagues reported last year that it failed to prevent development of severe inflammation in a mouse model of multiple sclerosis when administered by injection into the animals’ bellies. For groups less focused on specific molecules or mechanisms, there’s also the brute force approach to identifying promising worm-derived drugs. Loukas is doing this for the secretome of A. caninum: his team recently made recombinant versions of all 100 or so proteins they identified a decade ago and have been systematically testing them in a mouse model of IBD. “There’s a whole bunch of proteins that got a [check mark] in that screen, and some of them were things we might never have thought about beforehand,” says Loukas, who recently cofounded the startup Macrobiome Therapeutics to further his helminth-therapy work. (A previous startup Loukas cofounded, Paragen Bio, closed down last year.) “Now we’re trying to put together a preclinical program to assess those proteins in much greater depth,” he says, “and see which ones really are potentially drug-like and which ones will not be suitable.” He’s continuing to document worm secretions, too—a recent study identified nearly 200 proteins from N. americanus. Harnett says researchers may well discover more interesting worm-derived compounds in the future. “Any parasitic worm that you look at secretes a number of anti-inflammatory molecules,” he says. “Many species have yet to be examined, so it’s possible that there’s a lot of treasures we didn’t come across yet.” Indirect effects of helminth infection While most researchers in this field have been focusing on direct interactions between worms and their hosts, several who spoke to The Scientist highlighted an additional dimension to their work, one that acknowledges the trillions of bacteria occupying the same space a parasitic worm calls home. Increasingly seen as a mediator of human health in its own right, with hypothesized effects on everything from intestinal inflammation and immune development to cancer progression and mental health, the gut microbiome could also be an important piece of a worm’s relationship with its host. Nicola Harris, an intestinal immunologist at Monash University in Australia, has been delving into this tripartite relationship for years now. Part of her work examines how worms react to the gut microbiota; some of the team’s latest mouse data suggest that at least some worm species are “much, much happier without any bacteria around it at all,” Harris says. Another facet concerns the microbiome’s role in mediating helminth-host interactions—an issue with particular relevance for understanding the possible therapeutic effects of helminth infection. Indeed, work by several groups suggests that the microbiota seems to be required for some of the beneficial consequences of helminth infection. In one study, for example, Harris, Maizels, and colleagues reported that mice that were inoculated with H. polygyrus before being infected with a respiratory virus typically showed less lung inflammation than helminth-negative mice given the same virus, but this protective effect disappeared when the experiments were repeated with germ-free mice. Increasingly seen as a mediator of human health in its own right, the gut microbiome could also be an important piece ofa worm’s relationship with its host. One of the ways helminths might act on the host via the microbiota is by changing the overall composition of bacterial species in the gut—something that has frequently been linked to disease risk and health outcomes independent of helminth infection. Circumstantial evidence for this mechanism comes from observations of humans showing that worm-infected people have different microbiomes than uninfected people. For example, while Loke was working a few years ago in Malaysia, where he’s originally from, he tells The Scientist, he found that infection with Trichuris species was linked to greater phylogenetic diversity of bacteria in the gut. The results were interesting, Loke says, because parasitic infections—at least, harmful ones—are typically associated with lower bacterial diversity. In microbiome research, “there’s kind of a general impression that more diversity is better,” he says, adding that he and colleagues are now using meta-genomics and metatranscriptomic techniques to further characterize the microbiomes of helminth-infected people. Evidence for a potentially causal link comes from experimental work in animals and humans. Harris’s group has found that infection with helminths such as H. polygyrus can completely remodel the gut microbiota in mice, for example. And in a clinical trial of celiac patients carried out several years ago, Loukas and colleagues reported that experimental infection with N. americanus led to a small but statistically significant increase in the number of bacterial species detectable in the human gut, though community structure and bacterial diversity seemed broadly unaltered. Loke’s group is currently studying the countereffect: what happens to microbiota composition when helminth-positive people take deworming drugs. Worm infection may also favor the growth of specific types of bacteria over others, and in doing so, promote particular gut environments associated with disease or the absence of it. In 2016, for example, Loke and colleagues reported that mice that were genetically susceptible to developing Crohn’s disease had a lower risk of developing intestinal inflammation if they were infected with Trichuris muris, and that this protective effect occurred via the microbiota: helminth infection favored growth of bacteria in the Clostridiales order, which in turn kept a check on the inflammatory bacterial species Bacteroides vulgatus. (Loukas’s recent diabetes study also identified elevated abundance of Clostridiales in mice with N. brasiliensis infection, although it wasn’t clear if this aided in preventing disease.) Researchers including Harris suggest that this kind of microbiome involvement could help explain not only the putative health benefits of worm infection, but also the effects of worm-derived molecules. She highlights a 2019 study from Harnett’s group reporting that ES-62 protected mice from rheumatoid arthritis, an autoimmune disease that causes gradual bone erosion and that has previously been associated with disrupted gut microbiota. Monitoring the composition of the gut microbiome, the researchers also found that ES-62 treatment promoted growth of certain Clostridiales bacteria that produce butyrate, a metabolite previously shown to promote bone formation and prevent bone loss in mice. Causation couldn’t be established from the study, but Harris posed a question in a Nature perspective article accompanying the study’s publication: “Could interactions between gut parasites, such as helminths, and gut microbiota be the key to normalizing an unbalanced microbiome and preventing arthritis?” Relevant mechanisms could run both ways, she says—in some cases, the host immune response to helminths may alter the gut microbiota; in others, helminth-secreted products may alter microbiome composition directly, and subsequently affect host biology. Harnett says his group is delving further into this topic, adding that it’s possible that microbiome effects could help explain why ES-62 hasn’t proven to be very effective for some conditions such as type 1 diabetes. Loke notes that the microbiome could also contribute to variation among people and should be considered when trying to suss out who might benefit from particular helminth or helminth-derived therapies. This growing appreciation of microbes’ involvement in helminth-host interactions is a reminder of the complexity of the body’s biological community—and how much more there is to learn before worms or their derivatives can be widely deployed as therapeutic tools. The relatively recent discovery that worms secrete some of their proteins within extracellular vesicles that are taken up wholesale by host cells, for example, represents a previously unappreciated way for worms and hosts to communicate. Loukas also highlights what he says are intriguing findings about helminths’ effects on host brain chemistry, with a handful of small studies linking helminth infection with serotonin levels in mice. “It could well be that worms manipulate brain chemistry to make people . . . have a greater sense of well-being than an uninfected person,” he says. “That could be an evolutionary strategy: that the worms want you to feel good so that your life isn’t affected,” and you can transmit infection to others. Loukas speculates that such phenomena could even offer a possible explanation (other than placebo effects) for why many people report feeling so much better when infected, whether or not their disease improves clinically. Following one of the team’s celiac trials, some patients “had what a celiac pathologist would call fully blown disease, but these people didn’t feel unwell,” Loukas says. When trials end and participants are offered a deworming drug, many refuse it, he adds. “A number of people refer to [the worms] as their families.” And what about Loukas—would he kill off his parasites? “No!” he says. “I’m over fifty now and I felt like my knuckles were starting to feel slightly arthritic, and I thought ‘Oh, I wonder if the worms will do anything for them.’” Acknowledging that it’s just an anecdote, not a scientific insight, he says he thinks his knuckles have been feeling slightly better. “I don’t know if it’s due to the worms,” he says. “But I’m not getting rid of them in a hurry.” AGENT ON THE INSIDE Necator americanus COURTESY OF ALEX LOUKAS In addition to their potential as macrotherapeutics, helminths have caught the attention of organizations interested in developing ways to augment human biology. Alex Loukas and Paul Giacomin at James Cook University in Australia recently received funding to convert worms into “molecular foundries,” Loukas tells The Scientist. The project, supported by Charles River Analytics as part of a contract with the US government’s Defense Advanced Research Projects Agency (DARPA), aims to “take our worms, which have been shown to be safe and well-tolerated and can be genetically modified using techniques like CRISPR, and actually engineer them now to secrete therapeutic molecules that might combat bioterrorism agents like anthrax, or VX gas, or sarin gas,” he explains. The modified helminths could be then “used to infect soldiers or medical first responders who are working in areas where there is a bioterrorism agent threat.” The research could have applications beyond the battlefield, Loukas says, noting that the funding will help the teams establish proper development and manufacturing protocols that could advance the area of helminth therapy more generally. In the long run, he adds, it might even be possible to engineer worms to release drugs to combat disease. Before, you just had the parasites “in the body producing their own goodies, but now we can engineer them to secrete foreign molecules,” he says. “My goal one day is to have a worm that’s genetically modified to secrete an anti-inflammatory monoclonal antibody into the gut that might cure inflammatory bowel disease, for example.” Keywords: allergyautoimmune diseaseautoimmunitybiotherapeuticscell & molecular biologydrug designflatwormflatwormshelminthsimmune systemimmunologyinflammationmicrobiologyworm Related Articles Infographic: How Worms that Reside in the Gut Could Influence Health Tweak to N Protein Makes Delta Variant More Infectious Does Biological Sex Influence COVID-19 Outcomes? 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