Researchers uncover novel targets for treatment of schistosomiasis

The worms that cause schistosomiasis (Schistosoma mansoni) are unusual in several ways, especially the incontrovertible fact that female and male adults must stay paired together throughout their lives for replica to achieve success. Females may produce as many as 3,000 eggs per day. Roughly half reach the host’s gut or bladder. The remaining are swept away via the blood to the liver and spleen, where they cause severe inflammation and liver cirrhosis, the foremost reason behind mortality.

Researchers at Butantan Institute in São Paulo, Brazil, discovered a method to separate males from females, stopping reproduction and egg release. In an article published in PLOS Pathogens, they describe how they achieved this separation by silencing long non-coding RNAs, that are subsequently a promising goal for treating the disease.

Long non-coding RNAs (lncRNAs) are generally defined as transcripts with size larger than 200 nucleotides that will not be translated into protein.

“For a few years, lncRNAs were neglected by researchers despite the incontrovertible fact that they account for 97% of all of the RNA in human cells, because that they had no known functions. Within the last twenty years, cancer research above all has shown that when lncRNAs are dysregulated, they may cause disease. Our study shows for the primary time and in a functional manner that lncRNAs are essential to keep up homeostasis within the parasite that causes schistosomiasis and are subsequently potential therapeutic targets,” said Murilo Sena Amaral, co-corresponding writer of the article and a researcher at Butantan Institute’s Cell Cycle Laboratory.

The invention was a part of a Thematic Project, supported by FAPESP, to analyze the role of lncRNAs generally, using human cancer and Schistosoma worms as models. The principal investigator is Sergio Verjovski-Almeida, a professor on the University of São Paulo (USP) and a researcher at Butantan Institute. FAPESP also supported the study via 4 other projects (18/24015-0, 19/09404-3, 18/19591-2 and 16/10046-6).

Here it could be useful to recall that in humans, plants and animals (including parasites), all genetic information is contained in DNA, which serves as a kind of mold for the transcription of RNA within the cell nucleus. Verjovski-Almeida stressed that this sequence of events is referred to as the “central dogma of molecular biology”: genetic information flows only in a single direction, from DNA to RNA to protein, and proteins perform every kind of function in cells. Many of the RNA transcribed doesn’t translate into protein but plays vital roles in cellular processes, as research has shown in recent many years.

The researchers analyzed data from public repositories to discover the lncRNAs from S. mansoni that were most or least expressed when women and men were paired or separate after which used the outcomes to pick out three lncRNAs as candidate therapeutic targets.

“S. mansoni is well-adapted to living within the host’s mesenteric veins [which perfuse the intestines] and might remain there for many years if there is no such thing as a treatment. Pairing – the feminine living contained in the male – is crucial to their survival. Without it, they die, as we proved in our laboratory experiments,” Amaral said.

Separation and death

The researchers began with in vitro assays, placing pairs of female and male worms in culture dishes containing a medium with blood, and adding a molecule able to targeting the lncRNA of interest in order to cut back it within 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 within the parasite and results in its degradation. After a time, we found that the parasites that received the treatment separated, became less viable, stopped releasing eggs and died.”

Next, the researchers conducted experiments in mice infected by S. mansoni. They injected the identical double-stranded RNA into the animal’s bloodstream, and over time the goal lncRNA decreased within the parasites, resulting in their death and diminishing the viability of their eggs.

Neglected disease

Schistosomiasis is the foremost disease brought on by helminths (parasitic worms), affecting some 200 million people worldwide. Despite this significant prevalence, for 40 years praziquantel has been the one drug available to treat the disease.

In accordance with Verjovski-Almeida, praziquantel has major limitations. “It has been available on the market for a very long time with none alternatives, and there are reports of resistant worms. Hence the necessity to search out novel therapeutic targets against the disease. Our study proved that the parasites will be eliminated from the host’s bloodstream by attacking the pairing phenomenon. Our next step is to develop a drug that may do what the double-stranded RNA did in our study: silence expression of the lcnRNA within the parasite,” he said.