El-Amarna, Egypt; women and girls washing pots, pans and clothing in the Nile. Pans are dried on rock stands. The Nile and its man-made canals are the life-blood of Egypt but are also responsible for its most serious endemic disease, schistosomiasis. This is a parasitic infection carried by the Bilharzia worm (Schistosoma haematobium or Schistosoma mansoni) and spread to humans by water-dwelling snails. In 1990, about 25% of the total population of Egypt, including 36% of all villagers, did not have access to safe water for drinking and food preparation. [Carol Reeves. CC BY]
A natural chemical that can paralyze and stop infection by the parasitic worms that cause the devastating tropical disease schistosomiasis has been isolated from tiny aquatic animals called rotifers, by scientists at the Morgridge Institute.
The newly characterized tetracyclic alkaloid chemical, which lead investigator, Phillip Newmark, PhD, and his team have called schistosome paralysis factor (SPF), rapidly paralyzed free-living water-borne schistosome cercariae larvae, and prevented them from infecting mice.
The researchers say their characterization of SPF could help scientists to develop new drugs for treating schistosomiasis, which is also known as bilharzia. The neglected tropical disease affects hundreds of millions of people in Africa, Asia, and parts of South America. “Based on its ability to block infection, SPF holds great promise as an antischistosomal agent,” the investigators concluded in their published paper in PLOS Biology. “Identifying the biologically active chemical scaffolds and understanding SPF’s mode of action are expected to provide important clues for preventing schistosomiasis.” The researchers’ report is titled, “A rotifer-derived paralytic compound prevents transmission of schistosomiasis to a mammalian host.”
This movie shows the effects on cercariae of R. rotatoria-conditioned water (paralysis) vs. P. acuticornis-conditioned water (normal motility). [Phillip Newmark Lab, Morgridge Institute for Research]
Schistosomiasis is caused by parasitic flatworms of the genus Schistosoma. More than 200 million people are affected globally—commonly children—and 700 million are at risk of infection with schistosome parasites. The disease is second only to malaria in terms of numbers of people infected worldwide. The World Health Organization estimates that roughly 280,000 people die annually from schistosomiasis.
There is currently only one drug, praziquantel, for treating schistosome infection, and this is given to millions of school children each year. However, the drug only kills adult schistosomes, and does not stop reinfection. “Any time you’re talking about treating that many people with just one drug and no alternative, you’re really concerned about the ability of the parasites to develop resistance,” Newmark said. “And that’s becoming more and more of an issue as the geographic range of the parasite may be spreading and hybrids between human- and livestock-infecting schistosome species are being reported.”
The schistosome parasite has a complicated life cycle, which alternates between an intermediate aquatic snail host, and the definitive mammalian host, via two, free-living, water-borne forms known as miracidia and cercariae. The cercariae larvae in contaminated water burrow through the skin of a host mammal, and migrate into and anchor onto the blood vessels that supply the liver. Once in the mammalian host, the larvae develop into adult schistosomes. The females release eggs that are either passed out of the body in feces or urine to continue the life cycle, or remain lodged in body tissues and organs such as the liver. The adults can live for decades in the body, producing hundreds to thousands of eggs daily. Children with schistosomiasis commonly develop anemia, malnutrition, and pervasive learning disabilities.
When released into water from the mammalian host, the schistosomes then infect freshwater snails as their intermediate hosts, in which they produce millions of the tiny fork-tailed cercariae, which are again released in the water. These cercariae seek out their mammalian hosts, which they infect by penetrating through the skin, and so continue the life cycle.
Interestingly, tiny aquatic animals known as rotifers also live on the same types of aquatic snails that the schistosomes use as their intermediate hosts, and back in 1981 researchers reported that these tiny animals can produce a chemical compound that paralyzes cercariae on contact. The investigators who made this observation noted that cercarial motility was affected not only by the presence of rotifers but also by the water in which rotifers had been living—rotifer-conditioned water—indicating that the rotifers release some sort of water-soluble molecules with paralytic activity. However, as the Newmark team pointed out, “Almost 40 years have passed since this important finding, yet this factor’s identity has remained a mystery.”
For their newly reported research, the Newmark lab and collaborators in the laboratory of Jonathan Sweedler, PhD, at the University of Illinois at Urbana-Champaign, set out to identify and hopefully characterize this mystery compound. “Encouraged by this anticercarial effect and its potential to prevent schistosome infection, we sought to purify this paralyzing agent,” they commented. They found that the compound was produced by one species of rotifer in particular, Rotaria rotatoria, and showed that cercariae exposed to R. rotaria-conditioned artificial pond water (APW) rapidly stopped swimming, became immobilized, and dropped to the bottom of the dish.
The team’s chemical analyses indicated that the SPF compound had a novel tetracyclic structure. Tests with different concentrations of SPF and structurally similar natural compounds from Streptomyces species of bacteria showed that the immobilizing effects on the cercariae were dose dependent. The higher the concentration of the compounds in the water, the greater the paralytic effects on the schistosome larvae.
Cercariae have a tail that is essential for swimming, and which provides the force to enable the parasite to penetrate the skin. To see whether SPF would also stop infection by the larvae, they treated the cercariae with different concentrations of SPF and then exposed mouse tails to the treated parasites. Encouragingly, while untreated control cercariae readily infected the mice, none of the rodents exposed to the SPF-treated cercaria became infected.
Newmark, a professor of integrative biology at the University of Wisconsin-Madison and an investigator of the Howard Hughes Medical Institute, suggested the results could open a promising new path to controlling schistosomiasis. One particularly interesting observation is that the SPF structure resembles serotonin, a neurotransmitter most widely known for regulating mood. But serotonin also has an impact on normal neuromuscular function and SPF may be interfering with that pathway. “In schistosomes, serotonin has been implicated in neuromuscular functions in multiple life cycle stages,” the researchers commented. “Interestingly, praziquantel partially activates the human serotonin receptor, HT2BR, suggesting that it may also target schistosome serotonergic GPCRs.”
The authors acknowledge it’s not known why R. rotatoria produces SPF. Given that the compound has a structure that is similar to the Streptomyces-produced compounds, there’s also a possibility that SPF may actually be produced by the rotifer’s microbiota. “Whether SPF is used naturally to combat other aquatic creatures (e.g., to prevent other rotifers from colonizing areas where R. rotaria live), and thus, the effect on schistosome cercariae is indirect, or whether SPF benefits the rotifer’s commensal host will require further study,” the team stated. “Because compounds with structural similarities to SPF are produced by Streptomyces sp., it will be important to examine the possibility that SPF is not directly produced by the rotifer but rather by constituent(s) of its own microbiome.” However, they point out, it’s also possible that through horizontal gene transfer R. rotatoria has acquired the capacity to produce SPF on its own. “Further work will help reveal the source of SPF and its biosynthetic pathway.”
The Newmark lab first started investigating schistosomes about ten years ago. The investigators’ primary focus had always been the study of planarians, flatworms that can regenerate their entire bodies from tiny fragments, but recognition of the many similarities between planarians and schistosomes led the scientists to apply more than two decades of knowledge about planarian cell and molecular biology to study their parasitic schistosome relatives.
“All the work that we’ve done has been driven by our curiosity about these amazing planarians and all the different things that they can do,” Newmark said. “But we now have a new end game: We could actually wind up helping people in a tangible way, on a scale that we could not have considered before.”
