Glycans from Fasciola hepatica Modulate the Host Immune Response and TLR-Induced Maturation of Dendritic Cells

Abstract

Helminths express various carbohydrate-containing glycoconjugates on their surface, and they release glycan-rich excretion/secretion products that can be very important in their life cycles, infection and pathology. Recent evidence suggests that parasite glycoconjugates could play a role in the evasion of the immune response, leading to a modified Th2-polarized immune response that favors parasite survival in the host. Nevertheless, there is limited information about the nature or function of glycans produced by the trematode Fasciola hepatica, the causative agent of fasciolosis. In this paper, we investigate whether glycosylated molecules from F. hepatica participate in the modulation of host immunity. We also focus on dendritic cells, since they are an important target of immune-modulation by helminths, affecting their activity or function. Our results indicate that glycans from F. hepatica promote the production of IL-4 and IL-10, suppressing IFNγ production. During infection, this parasite is able to induce a semi-mature phenotype of DCs expressing low levels of MHCII and secrete IL-10. Furthermore, we show that parasite glycoconjugates mediate the modulation of LPS-induced maturation of DCs since their oxidation restores the capacity of LPS-treated DCs to secrete high levels of the pro-inflammatory cytokines IL-6 and IL-12/23p40 and low levels of the anti-inflammatory cytokine IL-10. Inhibition assays using carbohydrates suggest that the immune-modulation is mediated, at least in part, by the recognition of a mannose specific-CLR that signals by recruiting the phosphatase Php2. The results presented here contribute to the understanding of the role of parasite glycosylated molecules in the modulation of the host immunity and might be useful in the design of vaccines against fasciolosis.

Author Summary

Fasciola hepatica is a helminth that infects mainly ruminants, causing great economic losses worldwide. Importantly, fasciolosis is also considered an emerging zoonosis with an increasing number of human infections globally. As other helminths, F. hepatica is able to regulate the host immune response favoring parasite survival in the host. In this work we investigated whether glycoconjugates produced by this parasite play a role in the host immune-regulation. Glycans, composed by carbohydrate chains, participate in important biological processes, but their role during Fasciola infection has not been previously addressed. We found that glycoconjugates are involved in the production of the regulatory cytokine IL-10 and in the production of the Th2-like cytokines IL-4. Furthermore, we found that they are also involved in the modulation of dendritic cell maturation, the most efficient antigen presenting cells. Indeed, the parasite is able to inhibit the maturation of dendritic cells in a process that is glycan-mediated and dependent on a mannose-specific receptor. In conclusion, our results highlight the importance of parasite glycoconjugates in the modulation of host immunity and might be applied in the design of vaccine strategies to prevent infection.