Schistosomal extracellular vesicle‐enclosed miRNAs modulate host T helper cell differentiation

Meningher, Tal; Barsheshet, Yiftah; Ofir-Birin, Yifat; Gold, Daniel; Brant, Boris; Dekel, Elya; Sidi, Yechezkel; Schwartz, Eli; Regev‐Rudzki, Neta; Avni, Orly; Avni, Dror

doi:10.15252/embr.201947882

Cited by 67 publications

(70 citation statements)

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“…Investigations of extracellular vesicles released by parasitic helminths showed they contain abundant miRNAs and that these exosome-derived miRNAs participate in parasite-driven immunoregulation. Recent studies found that S. japonicum miRNAs can be delivered to host macrophages and T helper cells, where they regulate macrophage proliferation and Th cells differentiation by altering target gene expression (42,43). In line with these studies, prediction of the interactions between microRNAs from Ts-EVs and murine host genes indicated that these microRNAs may play a vital role in the modulation of host immune system functions, such as antigen presentation and immune cell activation.…”

Section: Discussionmentioning

confidence: 81%

Extracellular Vesicles Derived From Trichinella spiralis Muscle Larvae Ameliorate TNBS-Induced Colitis in Mice

et al. 2020

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Helminths are masters at modulating the host immune response through a wide variety of versatile mechanisms. These complex strategies facilitate parasite survival in the host and can also be exploited to prevent chronic immune disorders by minimizing excessive inflammation. Extracellular vesicles (EVs) are small membrane-bound structures secreted by helminths which mediate immune evasion during parasite infection. The goal of this study was to investigate the immunoregulatory properties of Trichinella spiralis EVs (Ts-EVs) in a murine model of colitis. We found that Ts-EVs significantly ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Ts-EVs alleviated intestinal epithelium barrier damage, markedly reduced pro-inflammatory cytokine secretion and neutrophil infiltration, and upregulated immunoregulatory cytokine expression in colon tissue. Ts-EVs also modulated the adaptive immune response by influencing T-cell composition. The numbers of Th1 and Th17 cells in MLNs, as well as the expression levels of Th1/Th17-associated cytokines and transcription factors in colon were reduced. In contrast, Th2 and Treg cells were increased after Ts-EVs treatment. Furthermore, sequencing of EV-derived microRNAs (miRNAs) indicated that an array of miRNAs was involved in the regulation of the host immune response, including inflammation. These findings expand our knowledge of host-parasite interactions, and may help design novel and effective strategies to prevent parasite infections or to treat inflammatory diseases like IBD. Further studies are needed to identify the specific cargo molecules carried by Ts-EVs and to clarify their roles during T. spiralis infection.

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Section: Discussionmentioning

confidence: 81%

Extracellular Vesicles Derived From Trichinella spiralis Muscle Larvae Ameliorate TNBS-Induced Colitis in Mice

et al. 2020

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“…In this context, the SNARE family member vesicle associated membrane protein 2 (VAMP2) was recently found to play a likely role in tegument maintenance, glucose uptake and egg production in S. japonicum [81]. Moreover, because the contents of schistosomederived extracellular vesicles [82,83] have recently been found to modulate host immune cells to support parasite survival [84,85], developing an understanding of vesicle trafficking mechanisms in these worms is a priority.…”

Section: Discussionmentioning

confidence: 99%

Deep phosphoproteome analysis of Schistosoma mansoni leads development of a kinomic array that highlights sex-biased differences in adult worm protein phosphorylation

et al. 2020

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Although helminth parasites cause enormous suffering worldwide we know little of how protein phosphorylation, one of the most important post-translational modifications used for molecular signalling, regulates their homeostasis and function. This is particularly the case for schistosomes. Herein, we report a deep phosphoproteome exploration of adult Schistosoma mansoni, providing one of the richest phosphoprotein resources for any parasite so far, and employ the data to build the first parasite-specific kinomic array. Complementary phosphopeptide enrichment strategies were used to detect 15,844 unique phosphopeptides mapping to 3,176 proteins. The phosphoproteins were predicted to be involved in a wide range of biological processes and phosphoprotein interactome analysis revealed 55 highly interconnected clusters including those enriched with ribosome, proteasome, phagosome, spliceosome, glycolysis, and signalling proteins. 93 distinct phosphorylation motifs were identified, with 67 providing a 'footprint' of protein kinase activity; CaMKII, PKA and CK1/2 were highly represented supporting their central importance to schistosome function. Within the kinome, 808 phosphorylation sites were matched to 136 protein kinases, and 68 sites within 37 activation loops were discovered. Analysis of putative protein kinase-phosphoprotein interactions revealed canonical networks but also novel interactions between signalling partners. Kinomic array analysis of male and female adult worm extracts revealed high phosphorylation of transformation:transcription domain associated protein by both sexes, and CDK and AMPK peptides by females. Moreover, eight peptides including protein phosphatase 2C gamma, Akt, Rho2 GTPase, SmTK4, and the insulin receptor were more highly phosphorylated by female extracts, highlighting their possible importance to female worm function. We envision that these findings, tools and methodology will help drive new research into the functional biology of schistosomes and other helminth parasites, and support efforts to develop new therapeutics for their control.

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“…It could be that vaccination with the EV molecules described herein is eliciting similar immune mechanisms to engender the observed anti-fecundity effects, which may be manifesting in a reduction of the fitness and fecundity of adult worms and/or a shortening of the lifespan of eggs embolised in the tissues [91]. Further, the ability of antibodies against helminth EV proteins to block vesicle uptake, which has subsequent impacts on host cell immune effector mechanisms [20,98], provides a plausible mechanism for protective efficacy.…”

Section: Discussionmentioning

confidence: 99%

Schistosoma haematobiumextracellular vesicle proteins confer protection in a heterologous model of schistosomiasis

Mekonnen

Tedla

Pickering

et al. 2020

Preprint

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29Helminth parasites release extracellular vesicles which interact with the surrounding host 30 tissues, mediating host-parasite communication and other fundamental processes of 31 parasitism. As such, vesicle proteins present attractive targets for the development of 32 novel intervention strategies to control these parasites and the diseases they cause. Herein, 33 we describe the first proteomic analysis by LC-MS/MS of two types of extracellular 34 vesicles (exosome-like, 120k pellet vesicles and microvesicle-like, 15k pellet vesicles) 35 from adult Schistosoma haematobium worms. A total of 57 and 330 proteins were 36 identified in the 120k pellet vesicles and larger 15k pellet vesicles, respectively, and some 37 of the most abundant molecules included homologues of known helminth vaccine and 38 diagnostic candidates such as Sm-TSP2, Sm23, glutathione S-tranferase, saposins and 39 aminopeptidases. Tetraspanins were highly represented in the analysis and found in both 40 vesicle types. Vaccination of mice with recombinant versions of three of these 41 tetraspanins induced protection in a heterologous challenge (S. mansoni) model of 42 infection, resulting in significant reductions (averaged across two independent trials) in 43 liver (47%, 38% and 41%) and intestinal (47%, 45% and 41%) egg burdens. These 44 findings offer insight into the mechanisms by which anti-tetraspanin antibodies confer 45 protection and highlight the potential that extracellular vesicle surface proteins offer as 46 anti-helminth vaccines.47 48 Introduction 52Schistosomiasis is the second most important parasitic disease, only after malaria, 53 in terms of social, economic and public health impact [1]. Schistosoma haematobium, the 54 causative agent of urogenital schistosomiasis, is highly prevalent in 53 Middle East and 55 African countries [1] and it is also sporadically seen in India [2] and France [3]. Urogenital 56 schistosomiasis affects more than 90 million people, mostly in sub-Saharan Africa where 57 180 million inhabitants are at risk, and is responsible for 150,000 deaths per year [4]. 58Furthermore, the most common complications associated with this disease include 59 schistosomal haematuria, bladder wall pathology, hydronephrosis, and dysuria [4]. 60The current control programs against schistosomiasis are aimed at reducing the 61 morbidity caused by the parasite by regularly treating infected populations with 62 praziquantel [5]. Despite the efforts made to control this devastating disease, 63 schistosomiasis is still spreading to new geographical areas [3,6]. Furthermore, 64 praziquantel has shown reduced efficacy in field studies [7] and is not effective against 65 the immature stages of the parasite [8,9]. Hence, a vaccine that reduces disease severity 66 and/or reduces transmission is needed to control and eliminate schistosomiasis [10,11]. 67Despite efforts over decades, there is no licensed vaccine [1,12]. Even though various 68 vaccine candidates have advanced into clinical trials targeting Schistosoma mansoni, ...

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Schistosomal extracellular vesicle‐enclosed miRNAs modulate host T helper cell differentiation

Cited by 67 publications

References 91 publications

Extracellular Vesicles Derived From Trichinella spiralis Muscle Larvae Ameliorate TNBS-Induced Colitis in Mice

Extracellular Vesicles Derived From Trichinella spiralis Muscle Larvae Ameliorate TNBS-Induced Colitis in Mice

Deep phosphoproteome analysis of Schistosoma mansoni leads development of a kinomic array that highlights sex-biased differences in adult worm protein phosphorylation

Schistosoma haematobiumextracellular vesicle proteins confer protection in a heterologous model of schistosomiasis

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