Long non-coding RNAs are essential for Schistosoma mansoni pairing-dependent adult worm homeostasis and fertility

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Silveira, Gilbert O. ; Coelho, Helena S. ; Pereira, Adriana S. A. ; Miyasato, Patricia A. ; Santos, Daisy W. ; Maciel, Lucas F. ; Olberg, Giovanna G. G. ; Tahira, Ana C. ; Nakano, Eliana ; Oliveira, Maria Leonor S. ; Amaral, Murilo S. ; Verjovski-Almeida, Sergio

• Document type: Journal article
• Source: PLOS PATHOGENS; v. 19, n. 5, p. 30-pg., 2023-05-01.

Abstract

The trematode parasite Schistosoma mansoni causes schistosomiasis, which affects over 200 million people worldwide. Schistosomes are dioecious, with egg laying depending on the females' obligatory pairing with males. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with low or no protein-coding potential that have been involved in other species with reproduction, stem cell maintenance, and drug resistance. In S. mansoni, we recently showed that the knockdown of one lncRNA affects the pairing status of these parasites. Here, we re-analyzed public RNA-Seq data from paired and unpaired adult male and female worms and their gonads, obtained from mixed-sex or single-sex cercariae infections, and found thousands of differentially expressed pairing-dependent lncRNAs among the 23 biological samples that were compared. The expression levels of selected lncRNAs were validated by RT-qPCR using an in vitro unpairing model. In addition, the in vitro silencing of three selected lncRNAs showed that knockdown of these pairing-dependent lncRNAs reduced cell proliferation in adult worms and their gonads, and are essential for female vitellaria maintenance, reproduction, and/or egg development. Remarkably, in vivo silencing of each of the three selected lncRNAs significantly reduced worm burden in infected mice by 26 to 35%. Whole mount in situ hybridization experiments showed that these pairing-dependent lncRNAs are expressed in reproductive tissues. These results show that lncRNAs are key components intervening in S. mansoni adult worm homeostasis, which affects pairing status and survival in the mammalian host, thus presenting great potential as new therapeutic target candidates. Author summarySchistosoma mansoni is a parasite that causes schistosomiasis, affecting over 200 million people worldwide. Only one drug is available for treatment, and new therapeutic strategies are required. S. mansoni females need to be continuously paired with males to be sexually mature and to produce eggs that cause tissue pathology. Therefore, interfering with adult worm pairing may provide new therapeutic intervention alternatives. However, the entire set of factors driving this pairing status are not fully understood. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with low or no protein coding potential. They have been shown in other species to be involved with reproduction. Here, we show that lncRNAs are essential for S. mansoni pairing-dependent adult worm homeostasis and/or fertility. We found that hundreds of lncRNAs are differentially expressed between paired and unpaired adult worms. We show by in vitro and in vivo gene silencing approaches that lncRNAs are essential to regulate the cell proliferation status of adult worm and their gonads, and to maintain worm pairing, female reproductive capacity, and/or egg development. Our study shows that lncRNAs are key components intervening in S. mansoni adult worm homeostasis, which affects pairing status and survival, thus presenting great potential as new therapeutic target candidates. (AU)

• FAPESP's process: 18/24015-0 - Functional characterization of long non-protein coding RNAs in Schistosoma mansoni
• Grantee: Gilbert de Oliveira Silveira
• Support Opportunities: Scholarships in Brazil - Doctorate