Large-scale RNAi screening uncovers therapeutic targets in the parasite Schistosoma mansoni

Abstract

Schistosome parasites kill 250,000 people every year. Treatment of schistosomiasis relies on the drug praziquantel. Unfortunately, a scarcity of molecular tools has hindered the discovery of new drug targets. Here, we describe a large-scale RNA interference (RNAi) screen in adult Schistosoma mansoni that examined the function of 2216 genes. We identified 261 genes with phenotypes affecting neuromuscular function, tissue integrity, stem cell maintenance, and parasite survival. Leveraging these data, we prioritized compounds with activity against the parasites and uncovered a pair of protein kinases (TAO and STK25) that cooperate to maintain muscle-specific messenger RNA transcription. Loss of either of these kinases results in paralysis and worm death in a mammalian host. These studies may help expedite therapeutic development and invigorate studies of these neglected parasites.

Daily rhythms in the transcriptomes of the human parasite Schistosoma mansoni

“…Consequently, there is a drive to develop a new generation of therapeutics based on schistosome genomes and their function (e.g. Berriman et al, 2009;Crosnier et al, 2020;Wang et al, 2020). Understanding the rhythms of target genes and their products will determine how an organ, or organism, will respond to a drug at a specific time of the day, and the timing of drug delivery could have a large impact on the effectiveness of target activation or inhibition (Cederroth et al, 2019).…”

“…Understanding the rhythms of target genes and their products will determine how an organ, or organism, will respond to a drug at a specific time of the day, and the timing of drug delivery could have a large impact on the effectiveness of target activation or inhibition (Cederroth et al, 2019). An RNAi screen to uncover new therapeutic targets in S. mansoni identified 195 genes that caused parasite detachment and affected survival (Wang et al, 2020), eight of which we have identified as diel genes (Additional file 1: Table S4), including Hsp90 (Smp_072330) that demonstrated very high amplitudes in both sexes. By searching the ChEMBL database (Mendez et al, 2019), we identified existing drugs that are predicted to target the encoded protein of 26 diel genes, 12 of which are phase IV approved drugs (i.e.…”

“…Drugs from the ChEMBL database that we predict to interact with the cycling genes were identified using the approach described in Wang et al (2020).…”

Lost and Found: Piwi and Argonaute Pathways in Flatworms

“…Consequently, this pathway has been exploited as a reverse genetic tool to silence specific genes (Han, 2018). Currently, more than two decades after it was first applied to a flatworm species (Sańchez Alvarado and Newmark, 1999), it is still the main tool to study gene function in worms (Mourão et al, 2012;Wang et al, 2020).…”

Genetic architecture of transmission stage production and virulence in schistosome parasites

“…These parasitic organisms are well suited for genetic studies because (i) the complete lifecycle can be maintained in the laboratory using rodent definitive hosts and freshwater snail intermediate hosts, (ii) parasites have separate sexes which simplifies staging of efficient genetic crosses in the laboratory, (iii) thousands of progeny are produced which provides good statistical power, and (iv) experimental work over the last 75 years has revealed heritable genetic variation in multiple biomedically important traits (Anderson et al, 2018) such as drug resistance (Cioli et al, 1992;Greenberg, 2013;Melman et al, 2009;Mwangi et al, 2014;Valentim et al, 2013), chronobiology (Théron, 2015;Théron andCombes, 1983, 1988), host specificity (Files and Cram, 1949;Kalbe et al, 2004;Mitta et al, 2017;Rollinson et al, 2001;Theron et al, 2014), and virulence (Davies et al, 2001;Gower and Webster, 2004;Webster et al, 2004). Furthermore, the Schistosoma mansoni genome is fully sequenced and assembled (Berriman et al, 2009;Protasio et al, 2012), and a growing molecular toolkit including molecular sexing tools (Chevalier et al, 2016;Gasser et al, 1991), RNAi (Krautz-Peterson et al, 2010), transfection (Mann et al, 2014;Rinaldi et al, 2012), CRISPR (Ittiprasert et al, 2019;Sankaranarayanan et al, 2020;You et al, 2021) and a suite of cell biology tools (Collins and Collins, 2017;Wang et al, 2020;Wendt et al, 2020;Wendt and Collins, 2016) improves our ability to link phenotype with genotype. Furthermore, we can also control the genetics of the snail host by generating inbred snail lines.…”