The Schistosoma mansoni T2 ribonuclease omega-1 modulates inflammasome-dependent IL-1β secretion in macrophages

Ferguson, Brian J.; Newland, Stephen A.; Gibbs, Sarah; Tourlomousis, Panagiotis; Santos, Paula Fernandes dos; Patel, Mitesh; Hall, Samuel W.; Walczak, Henning; Schramm, Gabriele; Haas, Helmut; Dunne, David W.; Cooke, Anne; Zaccone, Paola

doi:10.1016/j.ijpara.2015.08.005

Cited by 34 publications

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“…The ω1 ribonuclease alone is capable of conditioning human monocyte-derived dendritic cells to drive Th2 polarization (22) and enhanced CD11b + macrophage modulation of intracellular toll like receptor (TLR) signaling (30). Ribonuclease ω1 inhibited TLR-induced production of IL-1β and redirected the TLR signaling outcome towards an anti-inflammatory posture via the mannose receptor (MR) and dectin (22, 51, 52).…”

Section: Resultsmentioning

confidence: 99%

“…The T2 ribonuclease omega-1 (ω1) is the principal Th2-inducing component of ESP with its Th2-polarizing activity dependent upon both its RNase activity and glycosylation (19, 20, 28). This RNase is hepatotoxic (29), and its secretion by eggs into the granuloma regulates the pattern recognition receptor signaling pathways in dendritic cells that, in turn, prime Th2 responses from CD4 + T cells (30). Secreted ω1 provokes granulomatous inflammation around eggs traversing the wall of the intestines, and trapped in hepatic sinusoids and other host organs, driving fibrosis that eventually results in hepatointestinal schistosomiasis (1, 31).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Programmed genome editing of the omega-1 ribonuclease 1 of the blood fluke,Schistosoma mansoni

Ittiprasert

Mann

Karinshak

et al. 2018

Preprint

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34 35 CRISPR/Cas9 based genome editing has not yet been reported in schistosomes. Here, we tested 36 this approach by targeting omega-1 (ω1) of Schistosoma mansoni as a proof of principle. This 37 secreted ribonuclease is crucial for Th2 priming and granuloma formation, providing informative 38 immuno-pathological readouts for programmed genome editing. Schistosome eggs were either 39 exposed to recombinant Cas9 complexed with a synthetic guide RNA (sgRNA) complementary 40 to exon 6 of ω1 by electroporation or transduced with pseudotyped lentivirus encoding Cas9 and 41 the sgRNA. Some eggs were also transduced with a single stranded oligodeoxynucleotide donor 42 transgene that encoded six stop codons, flanked by 50 nt-long 5'-and 3'-microhomology arms 43 matching the predicted Cas9-catalyzed double stranded break (DSB) within ω1. CRISPResso 44 analysis of amplicons spanning the DSB revealed ~4.5% of the reads were mutated by insertions, 45deletions and/or substitutions, with an efficiency for homology directed repair of 0.19% insertion 46 of the donor transgene. Transcripts encoding ω1 were reduced >80%, and lysates of ω1-edited 47 eggs displayed diminished ribonuclease activity indicative that programmed editing mutated the 48 ω1 gene. Whereas soluble lysates of wild type eggs polarized Th2 cytokine responses including 49 IL-4 and IL-5 in human macrophage/T cell co-cultures, diminished levels of these cytokines 50followed the exposure to those of ω1-mutated schistosome eggs. Following injection of 51 schistosome eggs into the tail vein of BALB/c mice, the volume of pulmonary granulomas 52surrounding ω1-mutated eggs was 18-fold smaller than wild type eggs. Programmed genome 53 editing was active in schistosomes, Cas9-catalyzed chromosomal breakage was repaired by 54 homology directed repair and/or non-homologous end joining, and mutation of ω1 impeded the 55 capacity of schistosome eggs both to drive Th2 polarization and to provoke formation of 56 pulmonary circumoval granulomas. Knock-out of ω1 and the impaired immunological phenotype 57showcase the novel application of programmed gene editing in and functional genomics for 58 schistosomes. 59 60 61 Introduction 62 63Schistosomiasis is considered the most problematic of the human helminth diseases in terms of 64 morbidity and mortality [1][2][3][4]. The past decade has seen major advances in knowledge and 65 understanding of the pathophysiology, developmental biology, evolutionary relationships and 66 genome annotation of the human schistosomes [5][6][7][8][9][10][11][12][13][14][15][16]. Establishing CRISPR/Cas9 genome 67 editing in schistosomiasis would greatly enable effective functional genomics approaches. The 68 stable CRISPR/Cas9-based site-specific gene mutation and phenotyping will drive innovation 69 and a deeper understanding of schistosome pathogenesis, biology and evolution [17]. 70 71The schistosome egg plays a central role both in disease transmission and pathogenesis [1]. The 72 appearance of S. mansoni eggs in host tissues by six to seven week...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Programmed genome editing of the omega-1 ribonuclease 1 of the blood fluke,Schistosoma mansoni

Ittiprasert

Mann

Karinshak

et al. 2018

Preprint

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“…Notably, it has been shown that T2 ribonuclease omega-1 in soluble egg antigen is a major Th2 polarizing component, which is capable of regulating inflammasome activity [61]. It has been shown previously that VAL-5 is mainly present in the egg, miracidium and sporocyst developmental stages [62].…”

Section: Resultsmentioning

confidence: 99%

A next-generation microarray further reveals stage-enriched gene expression pattern in the blood fluke Schistosoma japonicum

et al. 2017

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BackgroundSchistosomiasis is caused by infection with blood flukes of the genus Schistosoma, and ranks, in terms of disability-adjusted life years (DALYs), as the third most important neglected tropical disease. Schistosomes have several discrete life stages involving dramatic morphological changes during their development, which require subtle gene expression modulations to complete the complex life-cycle.ResultsIn the current study, we employed a second generation schistosome DNA chip printed with the most comprehensive probe array for studying the Schistosoma japonicum transcriptome, to explore stage-associated gene expression in different developmental phases of S. japonicum. A total of 328, 95, 268 and 532 mRNA transcripts were enriched in cercariae, hepatic schistosomula, adult worms and eggs, respectively. In general, genes associated with transcriptional regulation, cell signalling and motor activity were readily expressed in cercariae; the expression of genes involved in neuronal activities, apoptosis and renewal was modestly upregulated in hepatic schistosomula; transcripts involved in egg production, nutrition metabolism and glycosylation were enriched in adult worms; while genes involved in cell division, microtubule-associated mobility, and host-parasite interplay were relatively highly expressed in eggs.ConclusionsThe study further highlights the expressional features of stage-associated genes in schistosomes with high accuracy. The results provide a better perspective of the biological characteristics among different developmental stages, which may open new avenues for identification of novel vaccine candidates and the development of novel control interventions against schistosomiasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1947-x) contains supplementary material, which is available to authorized users.

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“…The activation of Dectin-1 leads to the formation of a caspase-8 inflammasome, which mediates the cleavage of pro-IL-1β, leading to an increase in IL-1β secretion. In addition, further study has shown that omega-1 can induce the production of Foxp3 + Treg cells ( Ferguson et al, 2015 ).…”

Section: S Mansoni Soluble Egg Antigen (Sea)mentioning

confidence: 99%

Parasite-Derived Proteins for the Treatment of Allergies and Autoimmune Diseases

Wang

Tang

et al. 2017

Front. Microbiol.

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The morbidity associated with atopic diseases and immune dysregulation disorders such as asthma, food allergies, multiple sclerosis, atopic dermatitis, type 1 diabetes mellitus, and inflammatory bowel disease has been increasing all around the world over the past few decades. Although the roles of non-biological environmental factors and genetic factors in the etiopathology have been particularly emphasized, they do not fully explain the increase; for example, genetic factors in a population change very gradually. Epidemiological investigation has revealed that the increase also parallels a decrease in infectious diseases, especially parasitic infections. Thus, the reduced prevalence of parasitic infections may be another important reason for immune dysregulation. Parasites have co-evolved with the human immune system for a long time. Some parasite-derived immune-evasion molecules have been verified to reduce the incidence and harmfulness of atopic diseases in humans by modulating the immune response. More importantly, some parasite-derived products have been shown to inhibit the progression of inflammatory diseases and consequently alleviate their symptoms. Thus, parasites, and especially their products, may have potential applications in the treatment of autoimmune diseases. In this review, the potential of parasite-derived products and their analogs for use in the treatment of atopic diseases and immune dysregulation is summarized.

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The Schistosoma mansoni T2 ribonuclease omega-1 modulates inflammasome-dependent IL-1β secretion in macrophages

Cited by 34 publications

References 32 publications

Programmed genome editing of the omega-1 ribonuclease 1 of the blood fluke,Schistosoma mansoni

Programmed genome editing of the omega-1 ribonuclease 1 of the blood fluke,Schistosoma mansoni

A next-generation microarray further reveals stage-enriched gene expression pattern in the blood fluke Schistosoma japonicum

Parasite-Derived Proteins for the Treatment of Allergies and Autoimmune Diseases

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