Abstract
Fascioliasis, caused by the liver fluke Fasciola hepatica, is a neglected tropical disease infecting over 1 million individuals annually with 17 million people at risk of infection. Like other helminths, F. hepatica employs mechanisms of immune suppression in order to evade its host immune system. In this study the N-glycosylation of F. hepatica’s tegumental coat (FhTeg) and its carbohydrate-dependent interactions with bone marrow derived dendritic cells (BMDCs) were investigated. Mass spectrometric analysis demonstrated that FhTeg N-glycans comprised mainly of oligomannose and to a lesser extent truncated and complex type glycans, including a phosphorylated subset. The interaction of FhTeg with the mannose receptor (MR) was investigated. Binding of FhTeg to MR-transfected CHO cells and BMDCs was blocked when pre-incubated with mannan. We further elucidated the role played by MR in the immunomodulatory mechanism of FhTeg and demonstrated that while FhTeg’s binding was significantly reduced in BMDCs generated from MR knockout mice, the absence of MR did not alter FhTeg’s ability to induce SOCS3 or suppress cytokine secretion from LPS activated BMDCs. A panel of negatively charged monosaccharides (i.e. GlcNAc-4P, Man-6P and GalNAc-4S) were used in an attempt to inhibit the immunoregulatory properties of phosphorylated oligosaccharides. Notably, GalNAc-4S, a known inhibitor of the Cys-domain of MR, efficiently suppressed FhTeg binding to BMDCs and inhibited the expression of suppressor of cytokine signalling (SOCS) 3, a negative regulator the TLR and STAT3 pathway. We conclude that F. hepatica contains high levels of mannose residues and phosphorylated glycoproteins that are crucial in modulating its host’s immune system, however the role played by MR appears to be limited to the initial binding event suggesting that other C-type lectin receptors are involved in the immunomodulatory mechanism of FhTeg.
Highlights
Infection with parasitic worms modulates the host immune system by biasing T helper (Th) cells towards a Th-2/Treg immune response [1,2] while simultaneously impairing pro-inflammatory Th1/Th17 immunity
Fascioliasis, caused by the liver fluke Fasciola hepatica, is a neglected tropical disease infecting over 1 million individuals annually with 17 million people at risk of infection
F. hepatica’s tegumental coat (FhTeg) preparation is rich in oligomannose glycans and contains truncated complex type N-glycans with subsets substituted with negatively charged groups or α1-6-linked core fucosylation
Summary
Infection with parasitic worms (helminths) modulates the host immune system by biasing T helper (Th) cells towards a Th-2/Treg immune response [1,2] while simultaneously impairing pro-inflammatory Th1/Th17 immunity. This polarisation is due to the interaction of helminth derived molecules with pattern recognition receptors on innate immune cells such as dendritic cells, macrophages and mast cells that drive the polarisation of T-cells [3]. Helminth-derived glycoconjugates, i.e. N- and O-glycoproteins and glycolipids, often contain a mixture of glycan motifs similar or identical to those present in the host, and structurally distinct pathogen-related motifs [6]. While in most cases both glycans and proteins have a role to play [11,12,13,14,], some isolated glycan structures have been proven to directly activate host cells when presented as multivalent arrays on carrier proteins [15]
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