Booming Omics in Schistosoma

Efforts to eliminate schistosomiasis are hindered by incomplete efficacy of the only FDA-approved antischistosomal drug, praziquantel. By using postgenomic technologies, Wendt et al. and Wang deciphered function several genes required for worm survival pathogenesis, which opens way development innovative parasite-targeted therapies. Schistosomiasis — also known as bilharziasis is one most devastating world’s neglected tropical diseases that responsible considerable human morbidity. The etiological agents, schistosomes, dioecious flatworms reside permanently in copula within host's blood vessels. While feeding, females lay eggs majority become encysted surrounding host tissues organs (especially liver), causing pathology [1.Colley D.G. al.Human schistosomiasis.Lancet. 2014; 383: 2253-2264Abstract Full Text PDF PubMed Scopus (1212) Google Scholar]. Despite increased efforts eradicate over past five decades, more than 200 000 people still die each year from schistosome-associated complications [2.Chitsulo L. al.Schistosomiasis.Nat. Rev. Microbiol. 2004; 2: 12-13Crossref (215) This apparent failure control disease transmission is, part, due parasiticidal praziquantel, ineffective on immature worms does not prevent reinfection or emergence drug-resistant parasites. Accordingly, recently published roadmap, aiming at eliminating 2030, World Health Organization (WHO) highlights new treatments urgently needed [3.WHO/Department Control Neglected Tropical Diseases Ending Neglect Attain Sustainable Development Goals – A Road Map 2021–2030, WHO/UCN/NTD/2020.01.2020Google Hitherto, therapies has been hampered paucity molecular genetic tools exploring schistosome biology. In their two recent enlightening articles, [4.Wang J. al.Large-scale RNAi screening uncovers therapeutic targets parasite Schistosoma mansoni.Science. 2020; 369: 1649-1653Crossref (12) Scholar] [5.Wendt G. al.A single-cell RNA-seq atlas mansoni identifies a key regulator feeding.Science. 1644-1649Crossref (23) provide insights into functional biology schistosomes will undoubtedly unleash discovery potential drug targets. Indeed, despite tremendous advances both genome resources genetics few years (Figure 1), much cellular processes underpin tissue maintenance adult remain poorly understood. To gain better insight these processes, colleagues joining fluorescence-activated cell sorting (FACS), transcriptomics, situ hybridization successfully generate an unbiased classification subtypes male, mature female worms. approach enabled them produce precious ~43 high-quality cells (freely available SchistoCyte Atlasi), representing 68 transcriptionally distinct categories These clusters notably included neoblasts, motile stem involved turnover regeneration [6.Collins J.J. al.Adult somatic mansoni.Nature. 2013; 494: 476-479Crossref (133) Although previous studies indicated neoblasts predominantly serve tegument maintenance, there evidence other (e.g., planarians) have ‘specialized’ progenitors specific differentiated [7.Reddien P.W. basis planarian regeneration.Cell. 2018; 175: 327-345Abstract (85) Here, pointed out existence previously undescribed subpopulation cluster with gut cells, latter being digestion blood. combining RNA interference (RNAi) parasitological analyses, it was shown this neoblast ‘gut lineage’ expresses homolog hepatocyte nuclear factor 4 (hnf4), marker, planarians, preservation hematophagous behavior. silencing hnf4 resulted sizeable drop number luminal microvilli, leading morphological abnormalities subsequent inability parasites digest red absorb nutrients. Considering importance feeding production eggs, hallmarks pathology, further evaluated pathogenicity whose gene knocked down through RNAi. striking vivo experiment, demonstrated loss confers reduced (i.e., egg-induced granulomas) following surgical transplantation Schistosoma-naive mice. Moreover, RNAi-treated were significantly shorter nontreated controls, indicating normal growth. Taken together, data suggest targeting blood-feeding machinery may constitute relevant alternative strategy Another study, conducted same research group, used high-throughput profiling essential landscape identification novel S. approach, present dataset 2000 (~20% protein-coding genes), 261 assigned parasite’s critical repertoire. From list top candidates, couple serine/threonine kinases (TAO STK25) found be maintaining neuromuscular function. either kinase-encoding impaired locomotion, tetanic contraction body worm, detachment culture substrate. Most importantly, tao stk25 expression impeded capacity vessels, resulting attenuated pathology. noteworthy feature work elegant characterize large portion 195 designated attachment. transcriptomic analysis revealed substantial numbers related ubiquitin–proteasome pathway (UPP), maintains protein homeostasis functions eukaryotes [8.Collins G.A. Goldberg A.L. logic 26S proteasome.Cell. 2017; 169: 792-806Abstract (360) Strikingly, virtually all UPP elements led degeneration vitro, immobilization, even death underscores central role integrity schistosomes. larval stages [9.Bibo-Verdugo B. al.The proteasome target metazoan pathogen, mansoni.ACS Infect. Dis. 2019; 5: 1802-1812Crossref Scholar,10.Nabhan J.F. mansoni: bioinformatics analysis, developmental expression, studies.Exp. Parasitol. 2007; 117: 337-347Crossref (43) Scholar], then sought evaluate its druggability. filtering databases chemical libraries, series compounds therefore selected inhibit components. last exciting allowed p97, component UPP, development. sum, article sheds light usefulness large-scale unraveling complex pathways benefit field schistosomiasis. Altogether, illuminating articles unprecedented foundation understanding multiple aspects and, consequence, unveil hidden Notably, findings highlighted some pre-existing pharmacological thus accelerating unexpected highly effective anthelmintic compounds. It important underline value state-of-the-art methods here order identify clinical candidates selective activity (and limited side effects). One future avenue investigation concern reproductive egg production) because such intervention would combine advantage reducing limitation transmission. latest developments genomic technologies CRISPR-Cas9) stimulate fruitful area greatly help strategies. i www.collinslab.org/schistocyte/