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Biogenesis of extracellular vesicles. Broadly categorized, there are three types of vesicles: (A) Microvesicles are originated by outward budding and fusion of the plasma membrane; (B) exosomes arise from fusion of multivesicular bodies (MVB) with the plasma membrane. MVB derive from developing early to late endosomes. Inward budding of endosomal membrane forms intraluminal vesicle that are released upon fusion with the plasma membrane, (C) apoptotic blebs are released by cells undergoing apoptosis (modified from Gustafson et al. 2017)
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As part of the parasite’s excretory/secretory system, extracellular vesicles (EVs) represent a potent communication tool of schistosomes with their human host to strike the balance between their own survival in a hostile immunological environment and a minimal damage to the host tissue. Their cargo consists of functional proteins, lipids, and nucle...
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Parasites use different strategies of communication with their hosts. One communication channel that has been studied in recent years is the use of vesicle microRNAs to influence the host immune system by trematodes. sma-microRNA-10, secreted from Schistosoma mansoni, has been shown to influence the fate of host T-cells through manipulation of the...
Citations
... Therefore, each Schistosoma lifestage develops its own skills to communicate with the host via EVs for the maintenance of its biological functions. German reviewers [18] [18] . Diagnostic biomarkers: Due to implication of miR-191-5p in the pathogenesis of schistosomiasis japonicum, the study suggested its use as a potential prognostic biomarker [19] . ...
... Therefore, each Schistosoma lifestage develops its own skills to communicate with the host via EVs for the maintenance of its biological functions. German reviewers [18] [18] . Diagnostic biomarkers: Due to implication of miR-191-5p in the pathogenesis of schistosomiasis japonicum, the study suggested its use as a potential prognostic biomarker [19] . ...
... Therefore, bantam, miR-2c-3p, miR-3488, miR-142-3p and miR-223-3p were proposed diagnostic biomarkers with high sensitivity and specificity. Use of a miRNAs combination improved diagnostic accuracy compared to single miRNA, and proved valuable in grading hepatic fibrosis [18] . Potential therapeutic efficiency: Proteomic analysis of EVs derived from S. japonicum adults showed molecules with catalytic activity, and binding affinity and may therefore be considered as possible drug targets [19] . ...
... On the tegument, some large vesicles emerging and free vesicles were observed, with a size between 500 nm and 1,5 µm. Despite host immunomodulation passing through direct exocytosis of immunomodulatory substances among excretory/secretory products for the sporocysts (Dunn and Yoshino, 1988;Yoshino and Lodes, 1988;Lodes and Yoshino, 1989;Guillou et al., 2007), it is not excluded that the observed extracellular vesicles can have a role in host immunomodulation as for example through miRNA transport which is a reported phenomenon in the adult stage of schistosomes (Bischofsberger et al., 2020;Meningher et al., 2020;Li et al., 2022) or through other protein compounds released in extracellular vesicles such as Heat Shock Proteins (Acharya et al., 2021). Improvement of scanning electron microscopy technologies through the past forty years coupled to a CO 2 critical point drying method (osmium tetroxide post-fixation of biological samples is useless in scanning electron microscopy) permitted to obtain fairly good quality images. ...
The transformation of Schistosoma mansoni miracidia into mother sporocysts is induced, either in vivo by the penetration of the free-living larval stage, the miracidium, in the snail Biomphalaria glabrata or in vitro following the incubation of the miracidium in Chernin's Balanced Salt Solution (CBSS) or Bge (B. glabrata embryonic cell line) culture medium. The in vitro development of S. mansoni miracidium into mother sporocyst was monitored by Scanning Electron Microscopy (SEM) from 2.5 hours to 120 hours in CBSS. The transformation starts when the miracidium ciliate plates detach due to the proliferation of the intercellular ridge associated with the degeneration of mid-body papillae of the miracidium. The loss of ciliated plates causes the appearing of scars, filled across time by the proliferation of a new tegument originating from the interplate ridge. This new tegument covers the entire body of the metamorphosing parasite and differentiates over time, allowing some exchanges (uptakes or secretion/excretion) between the parasite and its host. In contrast to the well-described development of adult and free-living larval stages of S. mansoni using SEM, the developmental transformation of intramolluscan stages, especially tegumental changes in the mother sporocyst, has been sparcely documented at the ultrastructural level. In addition, taking into account the latest literature on miracidium electron microscopy and the advances in SEM technologies over the last thirty years, the present study gathers three main objectives: (i) Fill the gap of tegument scanning electron micrographs of in vitro transforming sporocysts; (ii) Update the current bibliographic miracidia and sporocysts image bank due to rapid evolution of SEM technology; (iii) Understand and describe the critical steps and duration of the in vitro miracidium-to-sporocyst transformation process to assist in understanding the interaction between the larval surface and snail immune factors.
... The highest lncRNA expression level in liver samples was veri ed in Sm-lncRNA 43 and Sm-lncRNA 55. In addition to these two molecules, Sm-lncRNA 19,24,25,31,37,44,48,54, and 59 also presented high expression levels in mouse liver samples. ...
... Finally, Sm-lncRNA 44 is involved in the vesicular fusion process. Extracellular vesicles are a known adaptative mechanism of S. mansoni developmental stages [36,37], which gives relevant value to Sm-lncRNA 44 experimental studies. In addition, Sm-lncRNA 44 presented a high expression level in all developmental stages evaluated here, and the same was observed in liver expression analysis, which increases the relevance of this molecule. ...
Background
Schistosomes infect over 200 million people, resulting in chronic disease and hundreds of thousands of deaths. It is believed that the complexity of the differentiation and developmental programs observed among the different developmental stages and in the environments where the parasite lives are influenced by the regulation of gene expression. In this scenario, long noncoding RNAs (lncRNAs) would be key molecules. Recently, our research group identified a set of 170 new lncRNAs in Schistosoma mansoni, and 15 were experimentally analyzed. Continuing this investigation, we evaluated the expression of 47 of these lncRNAs in S. mansoni developmental stages, as well as in liver samples of a murine schistosomiasis model.
Methods
We experimentally analyze 47 S. mansoni lncRNAs, and the validated ones had their expression analyzed using RT-qPCR in samples of the definitive-host-related developmental stages of the worm: cercariae, schistosomula 3.5 h, adult worms, and eggs; as well as in liver samples of BALB/c mice infected (100 cercariae) and uninfected, collected 9 weeks post-infection. Putative target protein-coding genes expression and Gene Ontology were collected in WormBase Parasite.
Results
We demonstrate that 25 of the 47 lncRNAs analyzed were primarily expressed in adult worms. 20 of these also show to be differentially expressed among the developmental stages evaluated, demonstrating that these molecules probably play a role in stage-specific gene expression. We also detect the expression of 22 S. mansoni-specific lncRNAs host liver samples, suggesting the action in the host-pathogen relationship. Finally, we describe lncRNA–protein coding gene correlations that identify lncRNAs with prospective roles in gene regulation.
Conclusions
Our results show clear differential expression patterns of lncRNAs in host-dependent development stages of S. mansoni and ascribe potential functional roles in development based on predicted intracellular interactions as well as potential for being biomarkers.
... EVs are secreted by almost all types of cells, and contents of EVs include proteins, lipids, polysaccharides, and other molecules such as nucleic acids (O'Brien et al., 2020). Schistosome EV microRNAs (miRNAs) cargo had been shown to modulate the host immune response (Liu et al., 2019;Bischofsberger et al., 2020;Meningher et al., 2020). Moreover, the contents of the EVs released within an infected host can serve as promising biomarkers for the disease diagnosis and help in understanding the infection-induced host pathology (Meningher et al., 2017;Cai et al., 2020). ...
Schistosoma is a genus of parasitic trematodes that undergoes complex migration in final hosts, finally developing into adult worms, which are responsible for egg production and disease dissemination. Recent studies documented the importance of extracellular vesicles (EVs) in the regulation of host-parasite interactions. Herein, we investigated the microRNA (miRNA) profiles of EVs isolated from host plasma at different stages of Schistosoma japonicum infection (lung stage: 3 days post-infection (dpi), and liver stages: 14 and 21 dpi) to identify miRNA cargo potentially involved in the pathogenesis and immune regulation of schistosomiasis. Characterization of the isolated plasma EVs revealed their diameter to be approximately 100 nm, containing typical EV markers such as Hsp70 and Tsg101. Deep sequencing analysis indicated the presence of 811 known and 15 novel miRNAs with an increasing number of differential miRNAs from the lung stage (27 miRNAs) to the liver stages (58 and 96 miRNAs at 14 and 21 dpi, respectively) in the plasma EVs of infected mice compared to EVs isolated from the uninfected control. In total, 324 plasma EV miRNAs were shown to be co-detected among different stages of infection and the validation of selected miRNAs showed trends of abundance similar to deep sequencing analysis. For example, miR-1a-3p and miR-122-5p showed higher abundance, whereas miR-150-3p and miR-126a showed lower abundance in the plasma EVs of infected mice at 3, 14, and 21 dpi as compared to those of uninfected mice. In addition, bioinformatic analysis combined with PCR validation of the miRNA targets, particularly those associated with the immune system and parasitic infectious disease, indicated a significant increase in the expression of Gbp7and Ccr5 in contrast to the decreased expression of Fermt3, Akt1, and IL-12a. Our results suggested that the abundance of miRNA cargo of the host plasma EVs was related to the stages of Schistosoma japonicum infection. Further studies on the roles of these miRNAs may reveal the regulatory mechanism of the host-parasite interaction. Moreover, the differentially abundant miRNA cargo in host EVs associated with S. japonicum infection may also provide valuable clues for identifying novel biomarkers for schistosomiasis diagnosis.
... Extracellular vesicles are small membrane-bound vesicular bodies released from cells. The vesicles are enriched for proteins in their external membrane and they carry cargos that include functional proteins, lipids and micro-RNAs (Bischofsberger et al., 2020). The most prominent function of extracellular vesicles (EVs) is in intercellular communication and it is hoped that an understanding of the molecular 'language' of the EV will bring new therapies for chronic human disease. ...
... Exosomes (25-100 nm diameter), the smallest of the vesicles, originate in endosomes. These bud to produce multivesicular bodies that migrate and fuse with the plasma membrane, liberating multiple exosomes (Bischofsberger et al., 2020). Microvesicles (>120 nm vesicles) are released directly by budding of the plasma membrane. ...
The unique multilaminate appearance of the tegument surface of schistosomes was first described in 1973, in one of the earliest volumes of the International Journal for Parasitology. The present review, published almost 50 years later, traces the development of our knowledge of the tegument, starting with those earliest cytological advances, particularly the surface plasma membrane-membranocalyx complex, through an era of protein discovery to the modern age of protein characterization, aided by proteomics. More recently, analysis of single cell transcriptomes of schistosomes is providing insight into the organization of the cell bodies that support the surface syncytium. Our understanding of the tegument, notably the nature of the proteins present within the plasma membrane and membranocalyx, has provided insights into how the schistosomes interact with their hosts but many aspects of how the tegument functions remain unanswered. Among the unresolved aspects are those concerned with maintenance and renewal of the surface membrane complex, and whether surface proteins and membrane components are recycled. Current controversies arising from investigations about whether the tegument is a source of extracellular vesicles during parasitism, and if it is covered with glycolytic enzymes, are evaluated in the light of cytological and proteomic knowledge of the layer.
... The infection course of schistosomiasis and the immune response of the host evolved in concert during continuing coevolutionary relationship that exerts selective pressures on the parasite for survival and reproduction without excessively harming its host, and on the host to expel the invasive parasite with a minimum collateral damage to its own tissues (Allen and Maizels, 2011). Parasites release biologically active molecules, and it is clear now that some of them are packed inside extracellular vesicles (EVs) (Coakley et al., 2015;Siles-Lucas et al., 2015;Eichenberger et al., 2018;Zakeri et al., 2018;Ofir-Birin and Regev-Rudzki, 2019;Bischofsberger et al., 2020). EVs are cellderived membrane-enclosed particles that varied by their size, content, and intra-cellular origin. ...
... Although very little is known about the functions of EVassociated miRNAs (Samoil et al., 2018;Bischofsberger et al., 2020), it is very likely that many of them are involved in the immune evasion. MiR-36-3p, miR-10-5p, miR-71a, miR-2162-3p and miR-61, were found in EVs from all stages of schistosomal development and have a known involvement in immune regulation. ...
Schistosomiasis (Bilharziasis), a neglected tropical disease that affects more than 240 million people around the world, is caused by infection with the helminth parasite Schistosoma. As part of their secretome, schistosomes release extracellular vesicles (EVs) that modulate the host immune response. The EV-harbored miRNAs upregulate the innate immune response of the M1 pathway and downregulate the differentiation toward the adaptive Th2 immunity. A schistosomal egg-derived miRNA increases the percentage of regulatory T cells. This schistosomal-inducible immunoediting process generates ultimately a parasitic friendly environment that is applied carefully as restrained Th2 response is crucial for the host survival and successful excretion of the eggs. Evidence indicates a selective targeting of schistosomal EVs, however, the underlying mechanisms are unclear yet. The effects of the schistosomes on the host immune system is in accordance with the hygiene hypothesis, attributing the dramatic increase in recent decades in allergy and other diseases associated with imbalanced immune response, to the reduced exposure to infectious agents that co-evolved with humans during evolution. Deciphering the bioactive cargo, function, and selective targeting of the parasite-secreted EVs may facilitate the development of novel tools for diagnostics and delivered therapy to schistosomiasis, as well as to immune-associated disorders.
... A glutamine synthetase has been described having high expression in the S. japonicum 21-day schistosomulum and adult worms of that and has been suggested as a drug target [47]. None of these three proteins have been identified in extracellular vesicles studies in our work [48]. ...
Schistosomiasis is a parasitic disease that affects 143 million people in endemic countries. This work analyzed overexpressed sequences from the cercaria phase to the early schistosomulum phase using bioinformatics tools to predict host interaction and selected proteins for predicting T cell epitopes. The final peptides were chemically synthesized, and their toxicity was evaluated in vitro. Peptides were formulated in the Adjuvant Adaptation (ADAD) vaccination system and injected into BALB/c mice that were challenged with S. mansoni cercariae to assess protection and immunogenicity. A total of 39 highly expressed S.mansoni proteins were identified as being of potential interest. Three T cell peptides predicted to bind MHC mouse and human class II were synthesized and formulated for vaccination. SmGSP and SmIKE reduced the number of eggs trapped in the liver by more than 50% in challenged BALB/c mice. The liver of mice vaccinated with either SmGSP or SmTNP had a significantly reduced affected liver surface. Transcriptome-based T cell peptides elicit partial protection and could be candidates for a multiantigen vaccine.
