Approaches to advance drug discovery for neglected tropical diseases

Drug Discovery Today, Год журнала: 2022, Номер 27(8), С. 2278 - 2287

Опубликована: Апрель 7, 2022

Язык: Английский

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Urogenital Schistosomiasis—History, Pathogenesis, and Bladder Cancer

Journal of Clinical Medicine, Год журнала: 2021, Номер 10(2), С. 205 - 205

Опубликована: Янв. 8, 2021

Schistosomiasis is the most important helminthiasis worldwide in terms of morbidity and mortality. Most infections occurs Africa, which about two thirds are caused by Schistosoma haematobium. The infection with S. haematobium considered carcinogenic leading to squamous cell carcinoma (SCC) urothelial urinary bladder. Additionally, it responsible for female genital schistosomiasis infertility higher risk human immunodeficiency virus (HIV) transmission. Remarkably, a recent outbreak Corsica (France) drew attention its potential re-mergence Southern Europe. Thus far, little known related host-parasite interactions that trigger carcinogenesis. However, studies have opened new avenues understand mechanisms on how parasite can lead cancer other associated pathologies. Here, we present historical perspective schistosomiasis, review infection-associated pathologies host–parasite unveil tentative underlying schistosomiasis-associated

Язык: Английский

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Vaccines for Human Schistosomiasis: Recent Progress, New Developments and Future Prospects

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(4), С. 2255 - 2255

Опубликована: Фев. 18, 2022

Schistosomiasis, caused by human trematode blood flukes (schistosomes), remains one of the most prevalent and serious neglected tropical parasitic diseases. Currently, treatment schistosomiasis relies solely on a single drug, anthelmintic praziquantel, with increased usage in mass drug administration control programs for disease, specter resistance developing is constant threat. Vaccination recognized as sustainable options any pathogen, but despite discovery reporting numerous potentially promising schistosome vaccine antigens, to date, no or animal deployment available. This fact that Science ranked such an intervention top 10 vaccines need be urgently developed improve public health globally. review summarizes current progress under clinical development advocates urgent establishment revolutionary effective anti-schistosome pipeline utilizing cutting-edge technologies (including mRNA exploiting CRISPR-based technologies) provide novel insight into future discovery, design, manufacture deployment.

Язык: Английский

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Improving helminth genome resources in the post-genomic era

Trends in Parasitology, Год журнала: 2022, Номер 38(10), С. 831 - 840

Опубликована: Июль 6, 2022

Genomics resources for helminth parasites are growing rapidly; however, it is still difficult to fully assemble a genome so most vary significantly in completeness and contiguity.Genome annotations rely heavily on computational prediction shared orthology between closely (and sometimes not closely) related species, which can result incomplete incorrect may bias against some genes, such as those that species-specific or phylogenetically restricted.New approaches required generate, improve, extend these valuable resources.Community-based efforts could build exploit different areas of specific expertise, from single genes whole gene families, provide iterative improvement centralised resources.Coordinated annotation will new opportunities interaction collaboration among the parasitology community. Rapid advancement high-throughput sequencing analytical has seen steady increase generation genomic parasites. Now, genomes their cornerstone numerous compare genetic transcriptomic variation, cells populations globally distributed parasites, modifications understand function. Our understanding helminths increasingly reliant resources, primarily static once published widely quality species. This article seeks highlight cause effect this variation argues continued – even after publication necessary more accurate complete biology important pathogens. In 2022, first gapless human assembly was [1.Nurk S. et al.The sequence genome.Science. 2022; 376: 44-53Crossref PubMed Scopus (168) Google Scholar], little than 20 years landmark completion draft announced [2.International Human Genome Sequencing Consortium Finishing euchromatic genome.Nature. 2004; 431: 931-945Crossref (3472) Scholar]. publicly available resource multinational collaborative arguably one our scientific achievements. The impact project extends far beyond itself; technological made during Project driven ever-increasing accessibility 'genomics' study structure, composition, function, evolution other, nonhuman Such advances now allow genome-sequencing projects be undertaken all over world potentially any organism with accessible DNA, routine experiments found modest molecular laboratory extreme environments [3.Castro-Wallace S.L. al.Nanopore DNA International Space Station.Sci. Rep. 2017; 7: 18022Crossref (177) Scholar] response disease [4.Volz E. al.Assessing transmissibility SARS-CoV-2 lineage B.1.1.7 England.Nature. 2021; 593: 266-269Crossref (463) cataloguing life Earth [5.Lewin H.A. al.Earth BioGenome Project: future life.Proc. Natl. Acad. Sci. U. A. 2018; 115: 4325-4333Crossref (352) parasitic worms, collectively termed helminths, benefited revolution. Often considered 'neglected' affect billion people living lowest-resource countries worldwide global livestock agriculture industries. Despite neglect, several sustained have been generate broad aims including parasite life-history traits [6.International Helminth Genomes Comparative genomics major worms.Nat. Genet. 2019; 51: 163-174Crossref (216) mining drug targets [7.Cotton J.A. Onchocerca volvulus, agent river blindness.Nat. Microbiol. 2016; 2: 16216Crossref (62) characterising resistance [8.Doyle S.R. Cotton Genome-wide investigate anthelmintic resistance.Trends Parasitol. 35: 289-301Abstract Full Text PDF (37) principal repository data, WormBase ParaSite [9.Howe K.L. al.WormBase − comprehensive genomics.Mol. Biochem. 215: 2-10Crossref (277) contains 210 (see Glossary) 169 species nematodes flatworms (WormBase release 17), representing pathogenic humans, animals, plants well comparison. These starting point many form scaffold upon 'omic analyses rely. Although intentionally provocative somewhat oversimplified, there truth statement; its hypothesis structure content within an they derived but, despite best efforts, rarely resemble product. For example, biologically, defined cell assembled into discrete chromosomes often not, represented informatically by contigs scaffolds number thousands 'completeness' Figure 1 comparison assemblies BUSCO [10.Manni M. al.BUSCO Update: novel streamlined workflows along broader deeper phylogenetic coverage scoring eukaryotic, prokaryotic, viral genomes.Mol. Biol. Evol. 38: 4647-4654Crossref (283) 17; 80.9% 1000 contigs/scaffolds). recent advancements make cheaper, easier, likely produce highly contiguous chromosome-scale assemblies, challenging finished eukaryotic helminths. A key challenge molecular/sequencing/analytical approach optimised organisms. large particularly complex (the median size 122.18 Mb, range 38.18 Mb Meloidogyne graminicola 1.25 Gb Spirometra erinaceieuropaei), helminth-focused further challenged factors. challenges include: (i) vast differences morphology tissue both (i.e., stages) require extraction lead efficiencies [11.Ayana al.Comparison four three preservation protocols detection quantification soil-transmitted stool.PLoS Negl. Trop. Dis. 13e0007778Google Scholar,12.Doyle al.Evaluation methods individual egg larval stages whole-genome sequencing.Front. 10: 826Crossref (17) Scholar]; (ii) inaccessibility larger mature also vivo stages, whereas juvenile eggs larvae typically microscopic environmentally resistant, limiting yield [12]; (iii) based host geographic location, infecting worldwide, human-infective incredibly access low-resource settings where commonly [13.Doyle al.Population ancient modern Trichuris trichiura.bioRxiv. https://doi.org/10.1101/2021.10.21.464505Crossref (0) if available, preserve high-quality samples (tissue DNA) cold-chain limited; (iv) high degree heterogeneity individuals which, pooling sufficient sequencing, artefacts [14.Doyle al.Genomic defines Haemonchus contortus, model gastrointestinal worm.Commun. 2020; 3: 656Crossref (36) Some addressed overcome developments very low-input concentrations [15.Kingan S.B. al.a de novo mosquito using pacbio sequencing.Genes. 62Crossref (66) specimen sequenced. Nonetheless, issues undoubtedly limited ability each existing achieve reference genome. only part puzzle. Once 'finished', then determine coordinates coding, noncoding other feature genome, followed attempt identify characterise function annotations. Several pipelines developed annotating (for see description 50 Helminths pipeline, applied at scale). contrast, use combination tools Augustus [16.Hoff K.J. Stanke Predicting AUGUSTUS.Curr. Protoc. Bioinform. 65e57PubMed Braker [17.Brůna T. al.BRAKER2: automatic GeneMark-EP+ AUGUSTUS supported protein database.NAR Genom. 3lqaa108PubMed Maker [18.Holt C. Yandell MAKER2: pipeline genome-database management tool second-generation projects.BMC 2011; 12: 491Crossref (987) PASA [19.Haas B.J. al.Improving Arabidopsis maximal transcript alignment assemblies.Nucleic Acids Res. 2003; 31: 5654-5666Crossref (950) Scholar]) combine various additional datasets, RNA-seq data homologous sequences evidence putative features predictions dependent assembly, type amount used, how representative mapped broadly good intron–exon splice junctions models; towards expressed, lowly expressed stage/condition were predicted reliably. While perform well, given evidence, under ideal scenario errors [20.Salzberg Next-generation annotation: we struggle get right.Genome 20: 92Crossref (105) Many evident until manually inspected, gene-by-gene, browser; coding 16 380 (ranging 8140 flexuosa 101 269 arenaria), trivial task. Unfortunately, generated scenario, fewer thoroughly interrogated manually. Examples include models fragmented multiple incorrectly merged, broken technical stop codons frameshifts, missing due lack divergence training dataset. complicate used define evolutionary functional relationships confounds estimates [21.Weisman C.M. al.Mixing comparative analysis inflates apparent lineage-specific genes.Curr. 32: 1-8Abstract (3) examples literature describe cloning validation identifying error resource; unfortunately, updated experimentally validated correct original resource. Further associated characterisation non-model organisms It recently estimated 47% families rendering 'hypothetical' [22.International Molecular Helminthology Annotation Network (IMHAN) al.Tackling hypotheticals genomes.Trends 34: 179-183Abstract do information relied computation inference homology information, thereof, interpreting difficult; region interest reveal list no known set enrichment biased functions common ontologies. Because immediately obvious, scale, research repeatedly and, consequently, benefit identified. Furthermore, limitations known, effort update therefore, impractical, especially genome-wide annotation. More necessarily solution, direct novel, parasite-specific roles needed [23.Viney failure biology.Trends 2014; 30: 319-321Abstract (12) deciphering role hypothetical proteins, enhanced 3D AlphaFold [24.Jumper J. al.Highly AlphaFold.Nature. 596: 583-589Crossref (4221) However, without improvements coordination feedback based, progress better ultimately limited. 'post-genomic' era, rate scale steadily [25.McVeigh P. Post-genomic parasitology.Parasitology. 147: 835-840Crossref (13) Genome-led include, transcription single-cell [26.Diaz Soria C.L. al.Single-cell atlas intra-mammalian developmental stage Schistosoma mansoni.Nat. Commun. 11: 6411Crossref (22) Scholar, 27.Wendt G. al.A mansoni identifies regulator blood feeding.Science. 369: 1644-1649Crossref (48) 28.Li conserved program controlling germline stem fate.Nat. 485Crossref (14) temporal [29.Rawlinson K.A. al.Daily rhythms expression mansoni.BMC 19: 255Crossref (5) spatially resolutions [30.Airs P.M. al.Spatial transcriptomics reveals antiparasitic essential behaviors Brugia malayi.PLoS Pathog. 18e1010399Crossref (2) large-scale RNAi screens [31.Wang al.Large-scale screening uncovers therapeutic mansoni.Science. 1649-1653Crossref (28) extensive family characterisation, chemoreceptors [32.Wheeler N.J. al.Genetic diversification chemosensory pathway receptors mosquito-borne filarial nematodes.PLoS 18e3000723Crossref small RNAs [33.Fontenla al.Lost found: Piwi Argonaute pathways flatworms.Front. Cell. Infect. 11653695Crossref (4) targeted modification transgenesis becoming efficient [34.Gang S.S. al.Targeted mutagenesis human-parasitic nematode.PLoS 13e1006675Crossref (69) 35.Ittiprasert W. al.Programmed editing omega-1 ribonuclease fluke, mansoni.eLife. 8e41337Crossref 36.Arunsan knockout mutation liver fluke granulin attenuates virulence infection-induced hepatobiliary morbidity.eLife. 8e41463Crossref (40) 37.Sankaranarayanan al.Large CRISPR-Cas-induced deletions oxamniquine locus parasite.Wellcome Open 5: 178Crossref (11) being complemented proteomics [38.Wang al.Somatic proteome contortus.Int. 49: 311-320Crossref (27) peptidomics [39.Buzy al.Peptidomics contortus.ACS Omega. 6: 10288-10305Crossref metabolomics [40.Kokova D. Mayboroda O.A. Twenty on: research.Trends 282-288Abstract lipidomics [41.Wang al.Helminth lipidomics: aspects prospects.Curr. Vector Borne 1100018Google generating 'omics problematic. problem assumption essentially 'correct' previous subheading); erroneous, biological insights surely missed or, worse, misinterpreted. second information-rich datasets significant potential add value but rarely, ever, so. largely that, published, change; whether primary synthesis remain distinct improve enrich based. Addressing two points focus time reference-quality (Figure 2). led fundamental resolution QTL contortus [42.Doyle modelling ivermectin nematode, contortus.BMC 218Crossref Scholar,43.Doyle landscape mediators resistance.bioRxiv. https://doi.org/10.1101/2021.11.12.465712Crossref sex malayi species) [44.Foster J.M. al.Sex chromosome humans.Nat. 1964Crossref delineation separate Z W [45.Buddenborg S.K. al.Assembled insight ZW sex-determination system.bioRxiv. https://doi.org/10.1101/2021.08.13.456314Crossref unusual centromere telomere structures ends Hymenolepis microstoma [46.Olson P.D. al.Complete representation tapeworm capped centromeres, necessitating dual segregation protection.BMC 18: 165Crossref demonstrate achieved measurable effects made. Therefore, question remains: (or should) done broadly, whom? (Box outlines access, synthesis, extension helminths). improvement, (as described above 2), groups working motivated question. currently, B. malayi, Strongyloides ratti, muris dedicated manual curation ongoing core group (which includes Caenorhabditis elegans, spp., Pristionchus pacificus), 2 describes H. annotation). remaining 95% ParaSite, scope seems less certain, relying curators unlikely diversity required. communities greater cumulative expertise; although contribute knowledge via resource, remains itself. opportunity needs taken advantage of. What currently lacking mechanisms easily transferred integrated dynamic change time. mechanism should scales, curating single-gene describing more. mechanism, when final product, seem therefore unachievable, already easy-to-use (e.g., Web Apollo [47.Dunn N.A. al.Apollo: democratizing annotation.PLoS Comput. 15e1006790Crossref (99) initiatives underway experts non-experts alike goal improving nematode Box trichiura pacificus annotations). platform integrate synthesise providing improved open restriction.Box 1Access, helminths1.Depositing open-access repositories•NCBIi: DNA/protein sequences, focussed genomes.•ENAii & SRAiii: raw reads, genomes, annotations.•WormBase ParaSiteiv: free-living platyhelminths.2.Synthesis resources•WormBase ParaSiteivoAlthough annotations, inferred UniProtv, specieso(Re-)integrates genomes/annotations become available. 17 species.oRuns Ensembl Compara sets refining genesets added.•AlphaFold Scholar]vi select worm proteomes, including: Dracunculus medinensis, mansoni, stercoralis, trichiura, Wuchereria bancrofti•Tools: gVAL [48.Howe K. al.Significantly through curation.GigaScience. 10giaa153Crossref G-OnRamp [49.Sargent L. al.G-OnRamp: Generating browsers facilitate undergraduate-driven 16e1007863Crossref Scholar].3.Development resources•Dedicated WormBasevii.oCurrently, six species.oCuration semi-automated, machine-learning components variants complement curation, reviewed [50.Davis 2022-data, processes, analyzing elegans.Genetics. 220iyac003Crossref Scholar].•Introduction technologies contiguity [e.g., conformation capture (HiC), optical mapping] long-read RNAseq, proteomics).oExamples: japonicum [51.Luo F. al.An japonicum.PLoS 13e0007612Crossref (29) haematobium [52.Stroehlein A.J. al.Chromosome-level underpins explorations variation.PLoS 18e1010288Crossref Sc

Язык: Английский

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Single-cell transcriptomics of the human parasite Schistosoma mansoni first intra-molluscan stage reveals tentative tegumental and stem-cell regulators

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Март 12, 2024

Abstract Schistosomiasis is a major Neglected Tropical Disease, caused by the infection with blood flukes in genus Schistosoma . To complete life cycle, parasite undergoes asexual and sexual reproduction within an intermediate snail host definitive mammalian host, respectively. The intra-molluscan phase provides critical amplification step that ensures successful transmission. However, cellular molecular mechanisms underlying development of stages remain poorly understood. Here, single cell suspensions from S. mansoni mother sporocysts were produced sequenced using droplet-based 10X Genomics Chromium platform. Six clusters comprising two tegument, muscle, neuron, parenchyma stem/germinal identified validated situ hybridisation. Gene Ontology term analysis predicted key biological processes for each clusters, including three sub-clusters. Furthermore, putative transcription factors tegument may play roles during interaction host.

Язык: Английский

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Functional genomics and the future of iPSCs in disease modeling

Stem Cell Reports, Год журнала: 2022, Номер 17(5), С. 1033 - 1047

Опубликована: Апрель 28, 2022

Induced pluripotent stem cells (iPSCs) are valuable in disease modeling because of their potential to expand and differentiate into virtually any cell type recapitulate key aspects human biology. Functional genomics genome-wide studies that aim discover genotype-phenotype relationships, thereby revealing the impact genetic diversity on normal pathophysiology. In this review, we make case iPSCs (hiPSCs) a powerful tool for functional genomics, since they provide an vitro platform study population genetics. We describe cutting-edge tools strategies now available researchers, including multi-omics technologies, advances hiPSC culture techniques, innovations drug development. approaches based hiPSCs hold great promise advancing discovery, etiology, variation

Язык: Английский

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Perspective on Schistosomiasis Drug Discovery: Highlights from a Schistosomiasis Drug Discovery Workshop at Wellcome Collection, London, September 2022

ACS Infectious Diseases, Год журнала: 2023, Номер 9(5), С. 1046 - 1055

Опубликована: Апрель 21, 2023

In September 2022, the Drug Discovery Unit at University of Dundee, UK, organised an international meeting Wellcome Collection in London to explore current clinical situation and challenges associated with treating schistosomiasis. The aim this was discuss need for new treatments view ascertain what key requirements would be any potential anti-schistosomals. This information will essential inform ongoing drug discovery efforts We also discussed pathway criteria progressing compounds clinic. To date, praziquantel (PZQ) is only available treat all species causing schistosomiasis, but it often unable completely clear parasites from infected patient, partially due its inactivity against juvenile worms. PZQ-mediated mass administration campaigns conducted endemic areas (e.g., sub-Saharan Africa, where schistosomiasis primarily prevalent) have contributed reducing burden disease not eliminate as a public health problem. Schistosoma develop resistance towards PZQ, sole treatment available, could become concern. Consequently, anthelmintic medications are urgently needed, Perspective aims capture some learnings our discussions on treatments.

Язык: Английский

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Transgenesis in parasitic helminths: a brief history and prospects for the future

Parasites & Vectors, Год журнала: 2022, Номер 15(1)

Опубликована: Март 28, 2022

Helminth infections impact the health of hundreds millions persons globally and also cause important economic losses in livestock farming. Methodological limitations as well low attention given to study helminths have impacted biological research and, thus, procurement accurate diagnosis effective treatments. Understanding biology using genomic proteomic approaches could contribute advances understanding host-helminth interactions lead new vaccines, drugs diagnostics. Despite significant genomics last decade, lack methodological adaptation current transgenesis techniques has hampered progression post-genomic helminthology. However, application techniques, such CRISPR, trematodes nematodes opened avenues for genome editing-powered functional these pathogens. This review summarises historical parasitic highlights pending that will need be overcome deploy tools.

Язык: Английский

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Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

PLoS Pathogens, Год журнала: 2022, Номер 18(1), С. e1009828 - e1009828

Опубликована: Янв. 13, 2022

α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins lipids. Mutations in the human genes encoding either enzyme lead to neurological neuromuscular impairments seen both Fabry- Schindler/Kanzaki- diseases. Here, we investigate whether parasitic blood fluke Schistosoma mansoni , neglected tropical disease schistosomiasis, also contains functionally important α-GAL α-NAGAL proteins. As infection, parasite maturation host interactions all governed carefully-regulated glycosylation processes, inhibiting S . mansoni’ s activities could development of novel chemotherapeutics. Sequence phylogenetic analyses putative α-GAL/α-NAGAL protein types showed Smp_089290 be only contain functional amino acid residues necessary substrate cleavage. Both enzymatic were higher females compared males ( p <0.05; > α-GAL), which was consistent with smp_089290 ’s female biased expression. Spatial localisation revealed accumulation parenchymal cells, neuronal vitellaria mature vitellocytes adult schistosome. siRNA-mediated knockdown (>90%) worms significantly inhibited activity when control siLuc treated males, <0.01; females, <0.05). No significant reductions observed same extracts. Despite this, decreases correlated a inhibition worm motility as well egg production. Programmed CRISPR/Cas9 editing confirmed reduction phenotype. Based these results, determined act predominantly an (hereafter termed SmNAGAL) schistosome parasites where it participates coordinating movement oviposition processes. Further characterisation SmNAGAL other may anthelmintic class compounds.

Язык: Английский

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Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

Frontiers in Cellular and Infection Microbiology, Год журнала: 2022, Номер 12

Опубликована: Окт. 28, 2022

Schistosomiasis has been widely disseminated around the world, and poses a significant threat to human health. Schistosoma eggs soluble egg antigen (SEA) mediated inflammatory responses promote formation of granulomas liver fibrosis. With continuous injuries stimulation, fibrosis can develop into cirrhosis cancer. Therefore, anti-fibrotic therapy is crucial increase survival rate patients. However, current research on antifibrotic treatments for schistosomiasis requires further exploration. In complicated microenvironment schistosome infections, it important understand mechanism pathology schistosomiasis-associated fibrosis(SSLF). this review, we discuss role SEA in inhibiting fibrosis, describe its mechanism, comprehensively explore host-derived schistosome-derived microRNAs (miRNAs) SSLF. Inflammasomes cytokines are factors promoting SSLF, mechanisms some critical signals pro-fibrotic cytokines. Natural killer(NK) cells killer T(NKT) inhibit SSLF but rarely described, therefore, highlight their significance. This summarizes provides insights key molecules involved development.

Язык: Английский

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