摘要：We have long known that parasitic worm infections are associated with lower rates of several conditions. Now, research in mice reveals how the worms elicit these protections

Parasitic worms modify immune cells in mice in a way that protects the animals from developing obesity, type 2 diabetes and heart disease. Future therapies that mimic these effects in humans could stave off such conditions.

It sounds strange, but researchers have known for decades that parasitic worm infections in humans and other animals are associated with lower rates of many diseases, including type 2 diabetes and heart disease. How worms elicit these protections remained a mystery until now.

Keke Fairfax at the University of Utah and her colleagues infected 10 male mice with the water-borne parasite Schistosoma mansoni and compared them with nine uninfected male animals. All mice ate a high-fat diet and had been bred to be genetically predisposed to obesity and cardiovascular disease.

After 10 weeks, the researchers harvested the animals’ bone marrow, which is where immune cells called monocytes develop. Monocytes can form into specialised white blood cells known as macrophages that engulf and digest pathogens. Previous research has shown that macrophages play a role in driving obesity-related insulin resistance and cardiovascular disease.

So, Fairfax and her colleagues cultivated bone marrow samples until macrophages formed. They then extracted these cells and placed them into a special machine that analysed their metabolism, which, for many immune cells, indicates how well they function, says Fairfax.

They found that, on average, macrophages from infected mice consumed about 25 per cent more oxygen while resting than those from uninfected animals. Their spare respiratory capacity – or ability to produce extra energy when needed – was also about 250 per cent greater than that of cells from uninfected mice. Both metrics signify parasitic worm infections improve how well macrophages function.

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Genetic analysis of macrophages from infected animals also showed changes in the activity of certain genes involved in regulating insulin and metabolising fats. Together, these findings suggest that parasitic worms protect their hosts from disease by altering gene expression in these kinds of white blood cells.

To confirm that, the team transferred bone marrow from mice infected with parasitic worms into eight uninfected male counterparts. After 10 weeks, these mice weighed less and had better blood sugar regulation than those that received bone marrow from uninfected animals.

“It could be that susceptibility to type 2 diabetes or other metabolic conditions is permanently changed by an episode like this. That’s really exciting,” says Rick Maizels at the University of Glasgow in the UK. “It accords the idea that [parasitic worm] infections in people have wide-ranging effects beyond the actual tissue or the location of the parasite itself.”

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“I’m obviously not out here recommending that everybody be infected with [parasitic worms] in order to reduce cardiometabolic diseases,” says Fairfax, who presented these findings on 11 April at a symposium hosted by the New York Academy of Sciences in New York City. “But if we can understand the mechanisms through which [parasitic worm] infection can give these benefits, we might have new pharmaceutical targets.” She and her colleagues are currently working to identify the molecule that these parasites produce to alter macrophage function. “I really see that as a potential therapeutic target,” she says.

This all makes sense from an evolutionary perspective as well. “Mammalian immunity evolved in the face of [parasitic worms], which are the most co-evolved pathogens,” said Fairfax. Over time mammals adapted to these worms’ presence, and Fairfax believes there is an advantage for worms too if their hosts are healthier, as they need the host to survive.

There appear to be limits to this symbiosis, however. When these experiments were repeated in female mice, there was no effect. Only when the animals’ ovaries were removed, causing the hormones oestrogen and progesterone to plummet, did they see that parasitic infection protected against disease. Researchers are now investigating why this might be, but in the first instance, this suggests that any future therapy mimicking the effect of parasitic worms won’t work in premenopausal women, says Fairfax.

Journal reference: Plos Pathogens DOI: 10.1371/journal.ppat.1009198