In 1981, scientists studying parasitic worms noticed something strange. A mysterious substance was paralyzing the worms, knocking out their ability to infect lab mice.

The scientists traced the mystery back to tiny aquatic animals called rotifers. If parasitic worms – blood flukes known as schistosomes – were exposed to rotifers, or even to water that had once held rotifers, the worms froze. The rotifers seemed to be producing some kind of paralytic agent.

Now, nearly 40 years later, Howard Hughes Medical Institute Investigator Phillip Newmark at the Morgridge Institute for Research at the University of Wisconsin-Madison and his team have identified and purified that paralytic substanceexternal link, opens in a new tab. Newmark’s team reports the work on October 17, 2019, in the journal PLOS Biology.

They hope to find a way to use the substance to combat schistosomiasis, one of the most common parasitic diseases in the world. Currently, there’s no vaccine for the disease, and treatment relies on one drug, praziquantel, for which schistosomes are showing signs of emerging resistance. What’s more, the drug acts only on the adult parasite after it has infected someone.

“We’d like to come up with ways to prevent an infection in the first place,” Newmark says.

Schistosomes have a complex life cycle, involving stages in snails and mammals, like mice or humans. Inside snails, schistosomes reproduce asexually, pumping out copies of themselves in what Newmark calls “industrial quantities.” These “terrifying little swimmers,” a larval form of the animal, are released from snails into bodies of freshwater, he says. There, humans can become infected while swimming or bathing.

Larvae penetrate skin, then circulate through the bloodstream, and eventually settle into the large blood vessels of the liver. There, the schistosomes mature into adult worms, which lay eggs that are shed in human feces or urine. When human waste contaminates fresh water, the eggs start the process all over again.

People with heavy infections of schistosomes can be anemic and chronically tired, and infected children can struggle in school. “One of the tragedies is that these are diseases of poverty that perpetuate poverty,” Newmark says. What’s more, infections can persist for decades and cause severe, or even fatal, liver damage.

The scientists who first noticed rotifers’ paralytic effect in 1981, led by Fred Lewis of the Biomedical Research Institute in Rockville, Maryland, tried to identify the mysterious compound but ran out of funding. Decades later, when Newmark decided to study schistosomes, he visited Lewis at the Schistosomiasis Resource Centerexternal link, opens in a new tab, and Lewis mentioned the rotifers. “I realized I could try to grow them myself to see if we could find this factor that Fred had identified,” Newmark says.

First, he grew the rotifer (Rotaria rotatoria) in artificial pond water in the lab and confirmed its effect on Schistosoma mansoni, one of several schistosome species that infect humans. Then he collaborated with chemist Jonathan Sweedler’s lab at the University of Illinois at Urbana-Champaign to isolate the paralytic compound.

The researchers determined the compound’s structure and purified it for further testing. They call it SPF, for Schistosome Paralysis Factor. Graduate student Jiarong Gao characterized SPF’s paralytic activity and showed that it can be used to prevent infection in mice.

Lewis says he’s “delighted” that Newmark decided to tackle this project. “Whether this finding leads to an additional strategy for combating schistosomiasis is a question worth pursuing,” Lewis says. “It may also stimulate new avenues of research into other, potentially medically important, products emitted by members of the phylum Rotifera.”

Next, Newmark’s team hopes to figure out how SPF exerts its paralytic effect. One clue: SPF has an unusual structure, and the only two compounds that are similar bind to receptors for the neurotransmitter serotonin. This suggests that SPF might be acting on serotonin receptors in the parasite, Newmark says. That could explain SPF’s paralytic effect, since serotonin is involved in controlling schistosomes’ movement.

Much work remains to figure out if SPF can be used to prevent schistosome infection outside of the lab, Newmark says, including whether the compound can be safely used on humans or if related compounds could be even more effective.

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Citation

Jiarong Gao et al. “A rotifer-derived paralytic compound prevents transmission of schistosomiasis to a mammalian hostexternal link, opens in a new tab.” PLOS Biology. Published online October 17, 2019. doi: 10.1371/journal.pbio.3000485