The worms that cause schistosomiasis (Schistosoma mansoni) are unique in many ways, most notably the fact that adult males and females must remain in pairs throughout their lives for successful reproduction. Females can produce up to 3,000 eggs per day. Approximately half reach the host’s gut or bladder. Some are swept through the blood into the liver and spleen, where they cause severe inflammation and cirrhosis of the liver, the leading cause of death.
Researchers at the Butantan Institute in São Paulo, Brazil, have discovered a way to separate males from females, preventing reproduction and egg release. In an article published in PLOS Pathogensthey describe how they achieve this separation by silencing long non-coding RNAs, which are therefore a promising target for disease treatment.
Long non-coding RNAs (lncRNAs) are generally defined as transcripts with a size greater than 200 nucleotides that are not translated into protein.
“For many years, lncRNAs have been overlooked by researchers despite the fact that they account for 97% of all RNA in human cells, because they have no known functions. In the last two decades, cancer research above all has shown that if lncRNAs are not regulated, they can cause disease.”
“Our study shows for the first time and in a practical way that lncRNAs are important to maintain the homeostasis of the parasite that causes schistosomiasis and are therefore potential therapeutic targets,” said Murilo Sena Amaral, co-author of the article and a researcher at the Butantan Institute’s Cell Cycle Laboratory.
The discovery is part of a Thematic Project to investigate the role of lncRNAs in general, using human cancer and Schistosoma worms as models. The principal investigator is Sergio Verjovski-Almeida, a professor at the University of São Paulo (USP) and a researcher at the Butantan Institute.
Here it may be useful to remember that in humans, plants and animals (including parasites), all genetic information is in DNA, which serves as a kind of mold for the transcription of RNA in the cell nucleus.
Verjovski-Almeida emphasized that this sequence of events is known as the “central dogma of molecular biology”: genetic information flows only in one direction, from DNA to RNA to protein, and proteins perform all kinds of functions in cells. Most of the RNA that is transcribed does not translate into protein but plays an important role in cellular processes, as research in recent decades has shown.
The researchers analyzed data from public repositories to identify lncRNAs from S. mansoni that were most or least expressed when males and females were mated or separated and then used the results to select three lncRNAs as candidate therapeutic targets.
“S. mansoni is well adapted to live in the mesenteric veins of the host [which perfuse the intestines] and can remain there for decades without treatment. Mating—the female living inside the male—is essential to their survival. Without it, they die, as we have proven in our laboratory experiments,” said Amaral.
Separation and death
The researchers began in vitro assays, placing pairs of male and female worms in culture dishes with a medium containing blood, and adding a molecule capable of targeting the lncRNA of interest to reduce it in the parasite.
“For proof of concept we used a double-stranded RNA molecule,” Amaral explained. “When added to the culture medium, it binds to the lncRNA of the parasite and leads to its degradation. After a time, we saw that the parasites that received the treatment separated, became less viable, stopped releasing eggs and died.”
Next, the researchers conducted experiments on mice infected with S. mansoni. They injected the same double-stranded RNA into the animal’s bloodstream, and over time the target lncRNA decreased in the parasites, leading to their death and reduced viability of their eggs.
It hurts to be neglected
Schistosomiasis is the main disease caused by helminths (parasitic worms), affecting about 200 million people worldwide. Despite this significant prevalence, for 40 years praziquantel was the only drug available to treat the disease.
According to Verjovski-Almeida, praziquantel has major limitations. “It has been on the market for a long time without any alternative, and there are reports of resistant worms. Hence the need to find a novel therapeutic target against the disease. Our study proves that the parasites can be eliminated from the host’s blood by attacking the pairing phenomenon. Our next step is to create a drug that can do what the double-stranded RNA expression of the LCRNA did in our study:
More information:
Gilbert O. Silveira et al, Long non-coding RNAs are essential for Schistosoma mansoni pairing-dependent adult worm homeostasis and fertility, PLOS Pathogens (2023). DOI: 10.1371/journal.ppat.1011369
Citation: Novel targets identified for the treatment of schistosomiasis (2023, July 24) retrieved 25 July 2023 from https://phys.org/news/2023-07-treatment-schistosomiasis.html
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