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      Bitter‐sweet symphony: glycan–lectin interactions in virus biology

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          Abstract

          Glycans are carbohydrate modifications typically found on proteins or lipids, and can act as ligands for glycan‐binding proteins called lectins. Glycans and lectins play crucial roles in the function of cells and organs, and in the immune system of animals and humans. Viral pathogens use glycans and lectins that are encoded by their own or the host genome for their replication and spread. Recent advances in glycobiological research indicate that glycans and lectins mediate key interactions at the virus‐host interface, controlling viral spread and/or activation of the immune system. This review reflects on glycan–lectin interactions in the context of viral infection and antiviral immunity. A short introduction illustrates the nature of glycans and lectins, and conveys the basic principles of their interactions. Subsequently, examples are discussed highlighting specific glycan–lectin interactions and how they affect the progress of viral infections, either benefiting the host or the virus. Moreover, glycan and lectin variability and their potential biological consequences are discussed. Finally, the review outlines how recent advances in the glycan–lectin field might be transformed into promising new approaches to antiviral therapy.

          Abstract

          Glycans and lectins cover crucial roles in virus biology and their interplay often shapes the virus‐host interaction. This review reflects on glycan‐lectin interactions in the context of viral infection and anti‐viral immunity, and explores potential targets for antiviral strategies.

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          Most cited references297

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          Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin.

          Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies. The structures of three conformations of the ectodomain of the 1968 Hong Kong influenza virus HA have been determined by X-ray crystallography: the single-chain precursor, HA0; the metastable neutral-pH conformation found on virus, and the fusion pH-induced conformation. These structures provide a framework for designing and interpreting the results of experiments on the activity of HA in receptor binding, the generation of emerging and reemerging epidemics, and membrane fusion during viral entry. Structures of HA in complex with sialic acid receptor analogs, together with binding experiments, provide details of these low-affinity interactions in terms of the sialic acid substituents recognized and the HA residues involved in recognition. Neutralizing antibody-binding sites surround the receptor-binding pocket on the membrane-distal surface of HA, and the structures of the complexes between neutralizing monoclonal Fabs and HA indicate possible neutralization mechanisms. Cleavage of the biosynthetic precursor HA0 at a prominent loop in its structure primes HA for subsequent activation of membrane fusion at endosomal pH (Figure 1). Priming involves insertion of the fusion peptide into a charged pocket in the precursor; activation requires its extrusion towards the fusion target membrane, as the N terminus of a newly formed trimeric coiled coil, and repositioning of the C-terminal membrane anchor near the fusion peptide at the same end of a rod-shaped molecule. Comparison of this new HA conformation, which has been formed for membrane fusion, with the structures determined for other virus fusion glycoproteins suggests that these molecules are all in the fusion-activated conformation and that the juxtaposition of the membrane anchor and fusion peptide, a recurring feature, is involved in the fusion mechanism. Extension of these comparisons to the soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) protein complex of vesicle fusion allows a similar conclusion.
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            Signalling through C-type lectin receptors: shaping immune responses

            Key Points Crosstalk between pattern recognition receptors (PRRs) expressed by dendritic cells orchestrates T helper (TH) cell differentiation through the induction of specific cytokine expression profiles, tailored to invading pathogens. C-type lectin receptors (CLRs) have an important role in orchestrating the induction of signalling pathways that regulate adaptive immune responses. CLRs can control adaptive immunity at various levels by inducing signalling on their own, through crosstalk with other PRRs or by inducing carbohydrate-specific signalling pathways. DC-specific ICAM3-grabbing non-integrin (DC-SIGN) interacts with mannose-carrying pathogens including Mycobacterium tuberculosis, HIV-1, measles virus and Candida albicans to activate the serine/threonine protein kinase RAF1. RAF1 signalling leads to the acetylation of Toll-like receptor (TLR)-activated nuclear factor-κB (NF-κB) subunit p65 and affects cytokine expression, such as inducing the upregulation of interleukin-10 (IL-10). DC-associated C-type lectin 1 (dectin 1) triggering by a broad range of fungal pathogens, such as C. albicans, Aspergillus fumigatus and Pneumocystis carinii, results in protective antifungal immunity through the crosstalk of two independent signalling pathways — one through spleen tyrosine kinase (SYK) and one through RAF1 — that are essential for the expression of TH1 and TH17 cell polarizing cytokines. Crosstalk between the SYK and RAF1 pathways is both synergistic and antagonizing to fine-tune NF-κB activity: although Ser276 phosphorylation of p65 leads to enhanced transcriptional activity of p65 itself through acetylation, it also inhibits the transcriptional activity of the NF-κB subunit RELB by sequestering it in p65–RELB dimers, which are transcriptionally inactive. The diversity in CLR-mediated signalling provides some major challenges for the researches to elucidate and manipulate the signalling properties of this exciting family of receptors. However, the recent advances strongly support the use of CLR targeting vaccination strategies using dendritic cells to induce or redirect adaptive immune responses as well as improve antigen delivery.
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              Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses.

              Contact between dendritic cells (DC) and resting T cells is essential to initiate a primary immune response. Here, we demonstrate that ICAM-3 expressed by resting T cells is important in this first contact with DC. We discovered that instead of the common ICAM-3 receptors LFA-1 and alphaDbeta2, a novel DC-specific C-type lectin, DC-SIGN, binds ICAM-3 with high affinity. DC-SIGN, which is abundantly expressed by DC both in vitro and in vivo, mediates transient adhesion with T cells. Since antibodies against DC-SIGN inhibit DC-induced proliferation of resting T cells, our findings predict that DC-SIGN enables T cell receptor engagement by stabilization of the DC-T cell contact zone.
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                Author and article information

                Journal
                FEMS Microbiol Rev
                FEMS Microbiol. Rev
                10.1111/(ISSN)1574-6976
                FMR
                FEMS Microbiology Reviews
                John Wiley and Sons Inc. (Hoboken )
                0168-6445
                1574-6976
                06 December 2013
                July 2014
                : 38
                : 4 ( doiID: 10.1111/fmr.2014.38.issue-4 )
                : 598-632
                Affiliations
                [ 1 ] Department of Virology, Parasitology and Immunology Faculty of Veterinary Medicine Ghent University Merelbeke Belgium
                [ 2 ] Infection Biology Unit German Primate Center Göttingen Germany
                [ 3 ] Department of Infectious Diseases and Immunology Faculty of Veterinary Medicine Utrecht University Utrecht The Netherlands
                Author notes
                [*] [* ] Correspondence: Wander Van Breedam, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.

                Tel.: +00 32 9 264 73 75;

                fax: +00 32 9 264 74 95;

                e‐mail: wander.vanbreedam@ 123456ugent.be

                Article
                FMR12052
                10.1111/1574-6976.12052
                7190080
                24188132
                887de615-4b4f-4d6e-a870-c38f3d5ede35
                © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                : 29 April 2013
                : 27 September 2013
                : 14 October 2013
                Page count
                Pages: 35
                Funding
                Funded by: Flemish Institute for the Promotion of Innovation by Science and Technology
                Award ID: SB 61491 & 63491
                Funded by: Special Research Fund of Ghent University
                Funded by: Leibniz Gemeinschaft
                Funded by: F.W.O.‐Vlaanderen
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                July 2014
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

                Microbiology & Virology
                dc‐sign,collectin,galectin,hemagglutinin,receptor‐destroying enzyme,antiviral

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