Schistosomal extracellular vesicle-enclosed miRNAs modulate host T helper cell differentiation
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Tal Meningher
PROVIDER: S-SCDT-EMBOR-2019-47882V1 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:During the chronic stage of Schistosoma infection, the female lays fertile eggs, triggering a strong anti-parasitic type 2 helper T-cell (Th2) immune response. It is unclear how this Th2 response gradually declines even though the worms live for years and continue to produce eggs. Here, we show that Schistosoma mansoni downregulates Th2 differentiation in an antigen-presenting cell-independent manner, by modulating the Th2-specific transcriptional program. Adult schistosomes secrete miRNA-harboring extracellular vesicles that are internalized by Th cells in vitro. Schistosomal miRNAs are found also in T helper cells isolated from Peyer's patches and mesenteric lymph nodes of infected mice. In T helper cells, the schistosomal miR-10 targets MAP3K7 and consequently downmodulates NF-?B activity, a critical transcription factor for Th2 differentiation and function. Our results explain, at least partially, how schistosomes tune down the Th2 response, and provide further insight into the reciprocal geographic distribution between high prevalence of parasitic infections and immune disorders such as allergy. Furthermore, this worm-host crosstalk mechanism can be harnessed to develop diagnostic and therapeutic approaches for human schistosomiasis and Th2-associated diseases.
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Project description:Schistosomiasis (Bilharziasis) is caused by the helminth Schistosoma. The acute stage of the infection extends from the penetration of the parasite through the host skin until it reaches its final location as adult female and male in copula, at the blood vessels around the gut or bladder. The female starts then depositing fertile eggs. The chronic stage of schistosomiasis starts with laying the eggs which promote a strong immunological Th2 response. It is unclear, so far, how this Th2 response gradually declines even though the parasitic worms live for years and continue to produce eggs. Here we demonstrate that schistosomes downregulate the differentiation toward the Th2 lineage by modulating the Th2 transcriptional program. Moreover, we found that adult schistosomes secrete micro-vesicles, possessing exosomal characteristics, and containing miRNAs, which have been found in Th2 cells that exposed indirectly to schistosomes. Importantly, we demonstrate that, the schistosoma miR-10 molecule targets MAP3K7, which consequently down modulates NF-kB. Since NF-kB is a critical factor necessary for Th2 differentiation and function, our results can at least partially explain, the decrease of the Th2 response over time of infection This exosomal worm-host immune cell interaction, can be further utilized for the development of novel diagnostic and therapeutic approaches to schistosomiasis.
2019-12-10 | PXD012525 | Pride
Project description:BackgroundSeveral studies in the past have investigated the expression of micro RNAs (miRNAs) in saliva as potential biomarkers. Since miRNAs associated with extracellular vesicles (EVs) are known to be protected from enzymatic degradation, we evaluated whether salivary EVs from patients with oral squamous cell carcinoma (OSCC) were enriched with specific subsets of miRNAs.MethodsOSCC patients and controls were matched with regards to age, gender and risk factors. Total RNA was extracted from salivary EVs and the differential expression of miRNAs was evaluated by qRT-PCR array and qRT-PCR. The discrimination power of up-regulated miRNAs as biomarkers in OSCC patients versus controls was evaluated by the Receiver Operating Characteristic (ROC) curves.ResultsA preliminary qRT-PCR array was performed on samples from 5 OSCC patients and 5 healthy controls whereby a subset of miRNAs were identified that were differentially expressed. On the basis of these results, a cohort of additional 16 patients and 6 controls were analyzed to further confirm the miRNAs that were up-regulated or selectively expressed in the previous pilot study. The following miRNAs: miR-302b-3p and miR-517b-3p were expressed only in EVs from OSCC patients and miR-512-3p and miR-412-3p were up-regulated in salivary EVs from OSCC patients compared to controls with the ROC curve showing a good discrimination power for OSCC diagnosis. The Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis suggested the possible involvement of the miRNAs identified in pathways activated in OSCC.ConclusionsIn this work, we suggest that salivary EVs isolated by a simple charge-based precipitation technique can be exploited as a non-invasive source of miRNAs for OSCC diagnosis. Moreover, we have identified a subset of miRNAs selectively enriched in EVs of OSCC patients that could be potential biomarkers.
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