Costs and benefits

Hookworm, one of humankind’s oldest foes, dwells in the ground, waiting quietly for its victims. This gape-mouthed parasite gains entry from warm, moist soils through bare feet; takes a trip through the lungs; and settles in the intestine to suck blood, often causing anemia, malnutrition, and stunted development. More than 500 million people worldwide are thought to be infected, mostly in Latin America, Africa, and Southeast Asia, and vaccination development and deworming solutions are underway.

But the hookworm and related parasitic worms, called helminths, may also have something to offer us. Infection can be protective in some circumstances, and Yale researchers are finding that the creatures can teach us how our immune systems self-regulate.

“These parasites have evolved over hundreds of thousands of years with their mammalian host. They understand each other extremely well,” says Michael Cappello, MD, a professor of pediatrics, of microbial pathogenesis, and of public health, who studies how nutrition influences susceptibility to worm infection, as well as the efficacy—or lack thereof—of treatment.

The human-worm relationship may be an agreement of sorts, Cappello suggests. “‘We’ll allow you in as long as you don’t cause too much disease and you don’t overwhelm us,’” he says, adding, “I think that we have evolved to harbor light worm infections.”

As evidence, Cappello explains that curing worm infections may not necessarily make a child healthier: “In some places, [mass deworming] has brought down the intensity of worm infections. But it’s been less clear that those reductions are actually associated with improved health.”

The worm might protect children from some of the worst effects of malaria. In 2007, Cappello studied anemia levels in Ghanaian children who were infected with malaria, hookworm, both, or neither. Having either one of the two infections rendered a child more likely to be anemic compared to uninfected children. With malaria, the anemia was especially severe. Paradoxically, though, having both infections at once does not multiply that likelihood, the team found. In fact, having both parasites resulted in less severe anemia than in victims suffering from just malaria.

“The combination of these two parasitic diseases is such that they actually in some ways kind of cancel each other out—and it may be that light hookworm infection blunts the response to malaria that leads to anemia,” Cappello says. “This was a surprising finding. … but it does add some supporting evidence to the idea that light worm infections may be beneficial.”

To be clear, that’s light infection. Moderate and heavy infections seem to do more harm than good, so it’s important to keep the worm under control. One major tool for doing this is mass drug administration, or deworming people en masse with a single dose of an antiparasitic drug like albendazole. But while this approach has been shown to reduce the prevalence of worm infections in some parts of the world, it doesn’t always work as expected.

In West Africa, for instance, Cappello’s team has found that mass drug administration has spotty efficacy.

“Some villages have a cure rate with albendazole that is 75 percent, whereas a few miles away a village showed a cure rate of zero,” Cappello says. The reasons have to do with the child’s nutritional status, the timing of treatment, and some worms’ genetic resistance to the drug, he believes.

So current worm control strategies may need to evolve, and Cappello wants to be ready. “Our lab and a small number of other groups around the world are trying to develop tools so that resistance can be detected when it emerges,” he says.

Hookworms are also chemistry wizards of sorts, manufacturing molecules that lead to profound effects in their hosts. They pump out anti-clotting molecules, for example, to keep their blood meals flowing (Cappello spent his early career purifying these molecules, one of which made it to human drug trials).

Perhaps more importantly, the worms also send molecular communications that regulate the immune system and ward off a strong attack. Carla Rothlin, PhD, is an associate professor of immunobiology and of pharmacology, who studies the immune system’s brakes—which molecules and pathways signal that it’s time to slow or stop an immune attack. One such brake is called the TAM receptor. The body can stimulate that receptor itself, but parasites can do it too. During an immune response to helminth infection, Rothlin’s lab has found that immune cells begin making massive amounts of a molecule called IL-4. That leads to the creation of a molecule called protein S, which plugs into TAM receptors and starts a negative feedback loop that calms the immune system.

Piecing together interactions like this one may shed light on the hygiene hypothesis—a way of explaining why, as sanitation improves and people are exposed to fewer microorganisms, their rates of allergy and autoimmune diseases go up. Researchers believe the immune system has evolved to anticipate its parasitic foes and even to rely on their tools for tamping down the immune system. When the parasite and its moderating influence are absent, we turn on ourselves.

This is the idea behind helminth therapy, in which worms are deliberately ingested to treat autoimmune and allergic diseases. Pig whipworm eggs have been studied as a treatment for inflammatory bowel disease, for example. Unable to develop to adulthood in humans, the eggs nonetheless deliver molecular messages to the human immune system that seem to curtail its propensity to attack itself. Intentional hookworm infections have also been investigated for allergic rhinitis.

But Rothlin believes it may be safer to pinpoint which molecules the worms use to talk to the immune system, then mimic that communication with drugs. This approach could replace potentially risky experiments with parasite infection—a practice “I would argue … can be very dangerous,” Rothlin says.

“Microorganisms are very good at this,” she adds. “For millions and millions of years, they have tried to usurp the regulatory pathways that we have. We can now study them, identify which molecules [they use, and] know more about the regulatory pathway itself. Microorganisms are great tools to understand immunology.”