Transformative tools for parasitic flatworms

doi:10.1126/science.abe0710

GSTDTAP > 气候变化

DOI	10.1126/science.abe0710
	Transformative tools for parasitic flatworms
	Timothy J. C. Anderson; Manoj T. Duraisingh
	2020-09-25
发表期刊	Science
出版年	2020
英文摘要	Schistosomes, a type of parasitic flatworm, are complex multicellular pathogens with an oversized and probably underestimated impact on human health. Schistosomiasis is one of the “neglected” tropical diseases, named in part because of a perceived lack of tools to probe parasite biology. On pages 1649 and 1644 of this issue, Wang et al. ([ 1 ][1]) and Wendt et al. ([ 2 ][2]), respectively, show that this neglect is unwarranted. With creative use of postgenomic and parasitological approaches, these authors uncover previously unknown aspects of schistosome biology, highlight avenues for intervention, and provide new resources for the field. Wang et al. report a loss-of-function screen that reveals numerous essential genes and identify small-molecule inhibitors of two kinases required for muscle development. Wendt et al. unveil a single-cell atlas for adult schistosomes, unearthing a gut stem cell lineage that can be targeted to eliminate egg production and pathology. Parasitic worms infect more than 1 billion people globally, particularly in resource-poor countries ([ 3 ][3]). They include parasites from two major phyla: the nematodes and platyhelminths (or flatworms—flukes and tapeworms). Parasitic worm infections cause anemia and stunting and impede cognitive development in children, affect the development of immunity and allergies, increase susceptibility to HIV and progression to AIDS, and result in many obstructive pathologies. Schistosome blood flukes infect more than 200 million people and cause widespread morbidity and more than 200,000 deaths globally every year ([ 4 ][4]). Schistosomes have complex life cycles and fascinating biology; they use both vertebrate and aquatic snail hosts and assume six morphologically distinct developmental, replicative, and sexual morphologies ([ 5 ][5]). In the human host, male and female adult schistosomes—the focus of the studies by Wang et al. and Wendt et al. —reside in pairs in the mesenteric veins around the intestines (see the micrograph, above) and can evade immune destruction for up to 40 years. During this time, they lay millions of eggs: Those that do not escape the body through feces or urine elicit strong host immune responses and cause severe pathology when lodged in host tissue ([ 6 ][6]). In the case of Schistosoma mansoni infections, granulomas form in the liver, leading to liver failure and death (see the micrograph, right). Interventions that eliminate adult worms or block egg production are required to prevent transmission and eliminate pathogenesis. Reducing infection, and pathology, of schistosomiasis relies on regular targeted or mass administration of the drug praziquantel (PZ), which was developed 50 years ago. However, PZ treatment typically leaves 30% of people positive for schistosome eggs, and the drug is ineffective against juvenile worms ([ 7 ][7]). Worryingly, resistance to PZ is suspected in the field ([ 8 ][8]) and is easily selected for in the laboratory ([ 9 ][9]). This makes the reliance on PZ monotherapy risky, and new interventions are needed, either to replace or to use in combination with PZ. Both Wang et al. and Wendt et al. provide a plethora of targets and pathways to prime a pipeline for therapeutic development. Fortunately, the complete life cycle of schistosome parasites—particularly S. mansoni , the focus of both studies—is easily maintained in the laboratory using rodent and snail hosts, there is a growing molecular and cell biological toolkit ([ 10 ][10], [ 11 ][11]), gene manipulation is possible ([ 12 ][12]), and genetic mapping studies can be conducted ([ 13 ][13]). Genome sequences are available for all three major species of schistosomes that infect humans and a growing number (>100) of other parasitic worm genomes, which facilitates comparative genomic studies to predict molecules and pathways of interest ([ 14 ][14]). Wang et al. and Wendt et al. exploit genomic information to develop two powerful approaches to functionally probe schistosome biology: large-scale RNA interference (RNAi) screens and single-cell gene expression atlases, respectively. Not only do the authors demonstrate the feasibility of applying these approaches to S. mansoni but they also conduct extensive functional analysis to reveal exciting features of parasite biology. Wang et al. targeted the expression of ∼2320 schistosome genes, of which 195 were critical for parasite attachment and 66 were critical for stem cell maintenance. They also identified a large number of genes that were essential for adult viability and development. Their analysis provides a treasure trove of possible therapeutic targets for further investigation and was enriched for genes in the ubiquitin proteasome system and muscle development. Many of the essential genes that were identified have orthologs that are not essential in model organisms, suggesting a distinctive biology of fluke parasites that cannot be inferred from studies of invertebrate model organisms, such as the nematode worm Caenorhabditis elegans or fruit flies ( Drosophila melanogaster ), or even from the free-living flatworm Schmidtea mediterranea . Although the functional RNAi screen identified a long list of essential genes, Wang et al. prioritized genes by examining the list for druggability with existing compounds. This allowed experimental validation of proteins involved in the ubiquitin proteasome system (p97) and muscle development (TAO and STK25 kinases) as drug targets. Small-molecule inhibitors with limited host toxicity were identified from a library of U.S. Food and Drug Administration–approved molecules, providing an impetus for drug development. Encouragingly, treatment with these small molecules resulted in worm mortality in vivo. Wendt et al. provide an elaborate picture of schistosome body structure and development through the creation of a single-cell atlas of schistosome adult parasites. The resolution is high, with 68 cell populations mapping to almost all of the known tissues of the worm, and spatial distributions of different cell lineages are described using in situ hybridization methods and electron microscopy. This descriptive work generates many tantalizing observations that will inspire future functional and cell biology analyses. There are lineages of ciliated neural cells with unknown functions, whereas other neural markers show left-right asymmetry in gene expression. In addition to identifying cells that make up key organs such as the nervous system and the sexual organs, the authors follow their fundamental interest in stem cells and examine the fate of a newly discovered stem cell lineage involved in gut formation. Detailed functional analysis reveals a central role for the hepatocyte nuclear factor 4 ( hnf4 ) gene not only in gut development but also in feeding and egg production. This study reveals gut development as a key point of intervention that results in a decrease in adult size and fecundity, eliminating the egg-induced pathology of schistosomiasis. Particularly powerful in these studies is the combination of new and old approaches to schistosome biology. Cioli et al. first showed that adult worms can be surgically implanted in rodents in the 1980s ([ 15 ][15]). By treating adult worms with RNAi in vitro and then implanting them in mice, both studies directly examine the impact of repressing the expression of specific genes on parasite survival within a host. Such strategic use of new and old methodologies makes a seemingly difficult organism extremely tractable. Researchers are now equipped with a long list of essential genes and a comprehensive single-cell atlas of adult worms for functional analysis and future screens. An immediate challenge is the prioritization of targets for drug development or as vaccine antigens, which will be based on criteria beyond essentiality. Are there conserved targets that are druggable at different development stages? Will population variation present a hurdle to effectiveness? One far-reaching impact will be the ability to translate insights from these screens to less experimentally and genetically tractable parasitic worms. This may be possible for the related flatworm parasites (tapeworms and other flukes) but will be more challenging for the more phylogenetically distant parasitic nematodes. The advent of postgenomic functional studies and tools in parasitic worms allows new comparative approaches. Rather than overzealous reliance on model organisms to infer aspects of parasite biology, it is now possible to directly compare developmental processes in parasites and their free-living relatives to examine how these organisms differ. Wang et al. and Wendt et al. go much further than identifying drug targets, supporting the premise that it is critical to understand the basic biology of pathogens before designing strategies to kill them. 1. [↵][16]1. J. Wang et al ., Science 369, 1649 (2020). [OpenUrl][17][Abstract/FREE Full Text][18] 2. [↵][19]1. G. Wendt et al ., Science 369, 1644 (2020). [OpenUrl][20][Abstract/FREE Full Text][21] 3. [↵][22]1. P. J. Hotez et al ., J. Clin. Invest. 118, 1311 (2008). 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/296474
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Timothy J. C. Anderson,Manoj T. Duraisingh. Transformative tools for parasitic flatworms[J]. Science,2020.
APA	Timothy J. C. Anderson,&Manoj T. Duraisingh.(2020).Transformative tools for parasitic flatworms.Science.
MLA	Timothy J. C. Anderson,et al."Transformative tools for parasitic flatworms".Science (2020).