Extracellular Vesicles From the Helminth Fasciola hepatica Prevent DSS-Induced Acute Ulcerative Colitis in a T-Lymphocyte Independent Mode

Abstract

The complexity of the pathogenesis of inflammatory bowel disease (ulcerative colitis and Crohn’s disease) has led to the quest of empirically drug therapies, combining immunosuppressant agents, biological therapy and modulators of the microbiota. Helminth parasites have been proposed as an alternative treatment of these diseases based on the hygiene hypothesis, but ethical and medical problems arise. Recent reports have proved the utility of parasite materials, mainly excretory/secretory products as therapeutic agents. The identification of extracellular vesicles on those secreted products opens a new field of investigation, since they exert potent immunomodulating effects. To assess the effect of extracellular vesicles produced by helminth parasites to treat ulcerative colitis, we have analyzed whether extracellular vesicles produced by the parasitic helminth Fasciola hepatica can prevent colitis induced by chemical agents in a mouse model. Adult parasites were cultured in vitro and secreted extracellular vesicles were purified and used for immunizing both wild type C57BL/6 and RAG1-/- mice. Control and immunized mice groups were treated with dextran sulfate sodium 7 days after last immunization to promote experimental colitis. The severity of colitis was assessed by disease activity index and histopathological scores. Mucosal cytokine expression was evaluated by ELISA. The activation of NF-kB, COX-2, and MAPK were evaluated by immunoblotting. Administration of extracellular vesicles from F. hepatica ameliorates the pathological symptoms reducing the amount of pro-inflammatory cytokines and interfering with both MAPK and NF-kB pathways. Interestingly, the observed effects do not seem to be mediated by T-cells. Our results indicate that extracellular vesicles from parasitic helminths can modulate immune responses in dextran sulfate sodium (DSS)-induced colitis, exerting a protective effect that should be mediated by other cells distinct from B- and T-lymphocytes.

Immunobiology of parasitic worm extracellular vesicles

“…Interestingly, in mice treated with EV‐depleted ESP fractions (secreted proteins only), IL‐10 was not elevated but the anti‐inflammatory cytokine TGFβ was increased compared to untreated mice that received TNBS alone, indicating that EVs and soluble ES proteins induce distinct anti‐inflammatory pathways . Similarly, EVs from the zoonotic liver fluke F. hepatica modulate immune responses in dextran sulfate sodium‐induced colitis, resulting in protection which is mediated by other cells distinct from B‐ and T lymphocytes . In this study, reduction in pro‐inflammatory cytokines interfering with both mitogen‐activated protein kinase and NF‐κB pathways was demonstrated.…”

Immunomodulation by Helminths: Intracellular Pathways and Extracellular Vesicles

“…A number of parasites have shown to release EVs and they have received great interest due to their remarkable immunomodulatory properties including suppression of IL-6, TNFα, and IL-17A in mice ( 191 , 199 , 200 ). Various potential mechanisms have been suggested through which these vesicles might affect host cells ( 201 ).…”

Fasciola hepatica Extracellular Vesicles isolated from excretory-secretory products using a gravity flow method modulate dendritic cell phenotype and activity

“…E. granulosus secretes EVs that are internalised by dendritic cells enhancing CD86 and MHC II expression on the cell surface [21]. Recently, Roig et al [26] showed that F. hepatica EVs modulate the activity of macrophages and DCs in addition to reducing the severity of DSS-induced colitis in mice suggesting that EVs contain potential biotherapeutic molecules. Many of these vesicles are targeted by antibodies isolated form infected animals [23,27] or animals vaccinated with EVs or EV-surface proteins [23,27] making them important vaccine candidates.…”