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.

A mucin-like peptide from Fasciola hepatica instructs dendritic cells with parasite specific Th1-polarizing activity

“…In contrast, many of them inhibited TLR-induced DC maturation212223242540. However, as reported by Falcon and colleagues26, the inhibitory effect exerted by F. hepatica molecules could be reverted when treatment with LPS was delayed.…”

“…Furthermore, DCs from mice infected with F. hepatica have a semi-mature phenotype that is characterized by low MHC II and CD40 expression and high secretion of the immunoregulatory cytokine IL-1025. Given their remarkable capacity to present antigens to T cells, antigen-loaded DCs have been proposed as vaccines to prevent a spectrum of infectious diseases2627282930.…”

Fasciola hepatica Immune Regulates CD11c+ Cells by Interacting with the Macrophage Gal/GalNAc Lectin

“…VVL recognized molecular components with an apparent molecular weight pattern similar to that observed for hMGL (Figures 3B,C). Moreover, preincubation with the lectin VVL, but not ConA, two lectins that strongly interact with FhTE (10), inhibited the hMGL recognition, suggesting that VVL and hMGL interact with the same ligands present in FhTE (Figure 3D).…”

Fasciola hepatica glycoconjugates immuneregulate dendritic cells through the Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin inducing T cell anergy

“…Very recent reports3334, including our own32, have brought insights about the role of F. hepatica glycans in mediating the regulation of DC-maturation through CLR recognition. Our group has recently described that glycan structures produced by F. hepatica participate in the modulation of bone marrow-derived DCs (BMDCs) and induce/mediate the production of IL-10 and IL-4 during infection32.…”

“…In addition, F. hepatica tegumental antigen modulates DC activity by suppressing MAPK-signaling and by up-regulating the expression of the suppressor of cytokine signaling 3 (SOCS3)31. Furthermore, we have demonstrated that DCs from mice infected with F. hepatica have a semi-mature phenotype that is characterized by low MHC II and CD40 expression and high secretion of the immunoregulatory cytokine IL-1032. Thus, it has been hypothesized that F. hepatica may modulate DC function and fate as a mean to control its pathogenesis and survival in the infected hosts.…”