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Special Issue "The Glycobiology of Viral Infections"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (28 February 2019)

Special Issue Editors

Guest Editor
Prof. Dr. Mario Schelhaas

University of Münster
Website | E-Mail
Interests: Virus entry, glycans, virus structure, virus-host interactions
Co-Guest Editor
Prof. Dr. Thomas H. Peters

University of Lübeck
Website | E-Mail
Interests: virus structure; glycans; NMR; carbohydrate chemistry
Co-Guest Editor
Prof. Dr. Laura Hartmann

University of Düsseldorf
Website | E-Mail
Interests: glycomacromolecules; macromolecular chemistry; polymer chemistry; polymeric biomimetics
Co-Guest Editor
Prof. Dr. Thilo Stehle

University of Tübingen
Website | E-Mail
Interests: virus structure; glycans; X-ray crystallography; virus-host interactions

Special Issue Information

Dear Colleagues,

All mammalian cells are covered in a layer of glycoconjugates—glycoproteins and glycolipids—known as the glycocalyx. Its glycans orchestrate diverse biological processes, including cell–cell recognition, cell growth and differentiation, neoplastic transformation and cell death. The glycocalyx also serves as a barrier against viruses and other intracellular pathogens, but is often utilized by such pathogens for attachment and entry (and is sometimes enzymatically processed during the release of progeny virus).

Many viruses make use of glycans as entry receptors (e.g., sialic acids, histo blood group antigens and glycosamino-glycans; caliciviruses, influenza viruses, polyomaviruses, and papilommaviruses) play critical roles in cell attachment and determining host range and tropism. 

The goal of this Special Issue is to highlight recent advances in the definition of parameters that guide virus- glycan binding and the impact on virus infection, and their use in the development of novel compounds with inhibitory and thus antiviral activities. Invited are structural and functional but also epidemiological studies that provide new insights into the biology of virus-glycan interactions, and the development of novel anti-virals that target these interactions.

All attendees of the International Symposium on Glycovirology 2018 will be granted a 10% discount in the Article Processing Charges (APCs) of their contributions.

Prof. Dr. Mario Schelhaas
Prof. Dr. Thilo Stehle
Prof. Dr. Laura Hartmann
Prof. Dr. Thomas H. Peters
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • glycan
  • virus structure
  • virus entry
  • virus host interactions
  • glycomimetics

Published Papers (9 papers)

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Research

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Open AccessArticle
Targeting Human Parainfluenza Virus Type-1 Haemagglutinin-Neuraminidase with Mechanism-Based Inhibitors
Viruses 2019, 11(5), 417; https://doi.org/10.3390/v11050417
Received: 1 March 2019 / Revised: 23 April 2019 / Accepted: 29 April 2019 / Published: 5 May 2019
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Abstract
Human parainfluenza virus (hPIV) infections are a major cause of respiratory tract illnesses in children, with currently no available vaccine or drug treatment. The surface glycoprotein haemagglutinin-neuraminidase (HN) of hPIV has a central role in the viral life cycle, including neuraminic acid-recognising receptor [...] Read more.
Human parainfluenza virus (hPIV) infections are a major cause of respiratory tract illnesses in children, with currently no available vaccine or drug treatment. The surface glycoprotein haemagglutinin-neuraminidase (HN) of hPIV has a central role in the viral life cycle, including neuraminic acid-recognising receptor binding activity (early stage) and receptor-destroying activity (late stage), which makes it an ideal target for antiviral drug disovery. In this study, we showed that targeting the catalytic mechanism of hPIV-1 HN by a 2α,3β-difluoro derivative of the known hPIV-1 inhibitor, BCX 2798, produced more potent inhibition of the neuraminidase function which is reflected by a stronger inhibition of viral replication. The difluorosialic acid-based inhibitor efficiently blocked the neuraminidase activity of HN for a prolonged period of time relative to its unsaturated neuraminic acid (Neu2en) analogue, BCX 2798 and produced a more efficient inhibition of the HN neuraminidase activity as well as in vitro viral replication. This prolonged inhibition of the hPIV-1 HN protein suggests covalent binding of the inhibitor to a key catalytic amino acid, making this compound a new lead for a novel class of more potent hPIV-1 mechanism-based inhibitors. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Open AccessCommunication
Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and Treatment
Viruses 2019, 11(5), 395; https://doi.org/10.3390/v11050395
Received: 1 April 2019 / Revised: 15 April 2019 / Accepted: 26 April 2019 / Published: 27 April 2019
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Abstract
Human adenoviruses (HAdV) are the most common cause of ocular infections. Species B human adenovirus type 3 (HAdV-B3) causes pharyngoconjunctival fever (PCF), whereas HAdV-D8, -D37, and -D64 cause epidemic keratoconjunctivitis (EKC). Recently, HAdV-D53, -D54, and -D56 emerged as new EKC-causing agents. HAdV-E4 is [...] Read more.
Human adenoviruses (HAdV) are the most common cause of ocular infections. Species B human adenovirus type 3 (HAdV-B3) causes pharyngoconjunctival fever (PCF), whereas HAdV-D8, -D37, and -D64 cause epidemic keratoconjunctivitis (EKC). Recently, HAdV-D53, -D54, and -D56 emerged as new EKC-causing agents. HAdV-E4 is associated with both PCF and EKC. We have previously demonstrated that HAdV-D37 uses sialic acid (SA)-containing glycans as cellular receptors on human corneal epithelial (HCE) cells, and the virus interaction with SA is mediated by the knob domain of the viral fiber protein. Here, by means of cell-based assays and using neuraminidase (a SA-cleaving enzyme), we investigated whether ocular HAdVs other than HAdV-D37 also use SA-containing glycans as receptors on HCE cells. We found that HAdV-E4 and -D56 infect HCE cells independent of SAs, whereas HAdV-D53 and -D64 use SAs as cellular receptors. HAdV-D8 and -D54 fiber knobs also bound to cell-surface SAs. Surprisingly, HCE cells were found resistant to HAdV-B3 infection. We also demonstrated that the SA-based molecule i.e., ME0462, designed to bind to SA-binding sites on the HAdV-D37 fiber knob, efficiently prevents binding and infection of several EKC-causing HAdVs. Surface plasmon resonance analysis confirmed a direct interaction between ME0462 and fiber knobs. Altogether, we demonstrate that SA-containing glycans serve as receptors for multiple EKC-causing HAdVs, and, that SA-based compound function as a broad-spectrum antiviral against known and emerging EKC-causing HAdVs. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Open AccessArticle
Histo-Blood Group Antigens in Children with Symptomatic Rotavirus Infection
Viruses 2019, 11(4), 339; https://doi.org/10.3390/v11040339
Received: 18 February 2019 / Revised: 26 March 2019 / Accepted: 9 April 2019 / Published: 10 April 2019
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Abstract
Group A rotaviruses are a major cause of acute gastroenteritis in children. The diversity and unequal geographical prevalence of rotavirus genotypes have been linked to histo-blood group antigens (HBGAs) in different human populations. In order to evaluate the role of HBGAs in rotavirus [...] Read more.
Group A rotaviruses are a major cause of acute gastroenteritis in children. The diversity and unequal geographical prevalence of rotavirus genotypes have been linked to histo-blood group antigens (HBGAs) in different human populations. In order to evaluate the role of HBGAs in rotavirus infections in our population, secretor status (FUT2+), ABO blood group, and Lewis antigens were determined in children attended for rotavirus gastroenteritis in Valencia, Spain. During three consecutive years (2013–2015), stool and saliva samples were collected from 133 children with rotavirus infection. Infecting viral genotypes and HBGAs were determined in patients and compared to a control group and data from blood donors. Rotavirus G9P[8] was the most prevalent strain (49.6%), followed by G1P[8] (20.3%) and G12P[8] (14.3%). Rotavirus infected predominantly secretor (99%) and Lewis b positive (91.7%) children. Children with blood group A and AB were significantly more prone to rotavirus gastroenteritis than those with blood group O. Our results confirm that a HBGA genetic background is linked to rotavirus P[8] susceptibility. Rotavirus P[8] symptomatic infection is manifestly more frequent in secretor-positive (FUT2+) than in non-secretor individuals, although no differences between rotavirus G genotypes were found. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Open AccessArticle
The CARD9-Associated C-Type Lectin, Mincle, Recognizes La Crosse Virus (LACV) but Plays a Limited Role in Early Antiviral Responses against LACV
Viruses 2019, 11(3), 303; https://doi.org/10.3390/v11030303
Received: 7 February 2019 / Revised: 22 March 2019 / Accepted: 25 March 2019 / Published: 26 March 2019
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Abstract
La Crosse virus (LACV) is a mosquito-transmitted arbovirus and the main cause of virus-mediated neurological diseases in children. To date, little is known about the role of C-type lectin receptors (CLRs)—an important class of pattern recognition receptors—in LACV recognition. DC-SIGN remains the only [...] Read more.
La Crosse virus (LACV) is a mosquito-transmitted arbovirus and the main cause of virus-mediated neurological diseases in children. To date, little is known about the role of C-type lectin receptors (CLRs)—an important class of pattern recognition receptors—in LACV recognition. DC-SIGN remains the only well-described CLR that recognizes LACV. In this study, we investigated the role of additional CLR/LACV interactions. To this end, we applied a flow-through chromatography method for the purification of LACV to perform an unbiased high-throughput screening of LACV with a CLR-hFc fusion protein library. Interestingly, the CARD9-associated CLRs Mincle, Dectin-1, and Dectin-2 were identified to strongly interact with LACV. Since CARD9 is a common adaptor protein for signaling via Mincle, Dectin-1, and Dectin-2, we performed LACV infection of Mincle−/− and CARD9−/− DCs. Mincle−/− and CARD9−/− DCs produced less amounts of proinflammatory cytokines, namely IL-6 and TNF-α, albeit no reduction of the LACV titer was observed. Together, novel CLR/LACV interactions were identified; however, the Mincle/CARD9 axis plays a limited role in early antiviral responses against LACV. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Open AccessArticle
Sulfated Glycosaminoglycans as Viral Decoy Receptors for Human Adenovirus Type 37
Viruses 2019, 11(3), 247; https://doi.org/10.3390/v11030247
Received: 21 February 2019 / Revised: 7 March 2019 / Accepted: 9 March 2019 / Published: 12 March 2019
Cited by 1 | PDF Full-text (5379 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Glycans on plasma membranes and in secretions play important roles in infection by many viruses. Species D human adenovirus type 37 (HAdV-D37) is a major cause of epidemic keratoconjunctivitis (EKC) and infects target cells by interacting with sialic acid (SA)-containing glycans via the [...] Read more.
Glycans on plasma membranes and in secretions play important roles in infection by many viruses. Species D human adenovirus type 37 (HAdV-D37) is a major cause of epidemic keratoconjunctivitis (EKC) and infects target cells by interacting with sialic acid (SA)-containing glycans via the fiber knob domain of the viral fiber protein. HAdV-D37 also interacts with sulfated glycosaminoglycans (GAGs), but the outcome of this interaction remains unknown. Here, we investigated the molecular requirements of HAdV-D37 fiber knob:GAG interactions using a GAG microarray and demonstrated that fiber knob interacts with a broad range of sulfated GAGs. These interactions were corroborated in cell-based assays and by surface plasmon resonance analysis. Removal of heparan sulfate (HS) and sulfate groups from human corneal epithelial (HCE) cells by heparinase III and sodium chlorate treatments, respectively, reduced HAdV-D37 binding to cells. Remarkably, removal of HS by heparinase III enhanced the virus infection. Our results suggest that interaction of HAdV-D37 with sulfated GAGs in secretions and on plasma membranes prevents/delays the virus binding to SA-containing receptors and inhibits subsequent infection. We also found abundant HS in the basement membrane of the human corneal epithelium, which may act as a barrier to sub-epithelial infection. Collectively, our findings provide novel insights into the role of GAGs as viral decoy receptors and highlight the therapeutic potential of GAGs and/or GAG-mimetics in HAdV-D37 infection. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Open AccessCommunication
Decoy Receptor Interactions as Novel Drug Targets against EKC-Causing Human Adenovirus
Viruses 2019, 11(3), 242; https://doi.org/10.3390/v11030242
Received: 25 February 2019 / Revised: 7 March 2019 / Accepted: 8 March 2019 / Published: 12 March 2019
Cited by 1 | PDF Full-text (2176 KB) | HTML Full-text | XML Full-text
Abstract
Epidemic keratoconjunctivitis (EKC) is a severe ocular disease and can lead to visual impairment. Human adenovirus type-37 (HAdV-D37) is one of the major causative agents of EKC and uses sialic acid (SA)-containing glycans as cellular receptors. Currently, there are no approved antivirals available [...] Read more.
Epidemic keratoconjunctivitis (EKC) is a severe ocular disease and can lead to visual impairment. Human adenovirus type-37 (HAdV-D37) is one of the major causative agents of EKC and uses sialic acid (SA)-containing glycans as cellular receptors. Currently, there are no approved antivirals available for the treatment of EKC. Recently, we have reported that sulfated glycosaminoglycans (GAGs) bind to HAdV-D37 via the fiber knob (FK) domain of the viral fiber protein and function as decoy receptors. Based on this finding, we speculated that GAG-mimetics may act as artificial decoy receptors and inhibit HAdV-D37 infection. Repurposing of approved drugs to identify new antivirals has drawn great attention in recent years. Here, we report the antiviral effect of suramin, a WHO-approved drug and a widely known GAG-mimetic, against HAdV-D37. Commercially available suramin analogs also show antiviral effects against HAdV-D37. We demonstrate that suramin exerts its antiviral activity by inhibiting the attachment of HAdV-D37 to cells. We also reveal that the antiviral effect of suramin is HAdV species-specific. Collectively, in this proof of concept study, we demonstrate for the first time that virus binding to a decoy receptor constitutes a novel and an unexplored target for antiviral drug development. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Open AccessArticle
Glycosylation of HIV Env Impacts IgG Subtype Responses to Vaccination
Viruses 2019, 11(2), 153; https://doi.org/10.3390/v11020153
Received: 22 January 2019 / Revised: 6 February 2019 / Accepted: 10 February 2019 / Published: 13 February 2019
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Abstract
The envelope protein (Env) is the only surface protein of the human immunodeficiency virus (HIV) and as such the exclusive target for protective antibody responses. Experimental evidences from mouse models suggest a modulating property of Env to steer antibody class switching towards the [...] Read more.
The envelope protein (Env) is the only surface protein of the human immunodeficiency virus (HIV) and as such the exclusive target for protective antibody responses. Experimental evidences from mouse models suggest a modulating property of Env to steer antibody class switching towards the less effective antibody subclass IgG1 accompanied with strong TH2 helper responses. By simple physical linkage we were able to imprint this bias, exemplified by a low IgG2a/IgG1 ratio of antigen-specific antibodies, onto an unrelated antigen, namely the HIV capsid protein p24. Here, our results indicate the glycan moiety of Env as the responsible immune modulating activity. Firstly, in Card9−/− mice lacking specific C-Type lectin responsiveness, DNA immunization significantly increased the IgG2a/IgG1 ratio for the Env-specific antibodies while the antibody response against the F-protein of the respiratory syncytial virus (RSV) serving as control antigen remained unchanged. Secondly, sequential shortening of the Env encoding sequence revealed the C2V3 domain as responsible for the strong IgG1 responses and TH2 cytokine production. Removing all potential N-glycosylation sites from the C2V3 domain by site-specific mutagenesis reversed the vaccine-induced immune response towards a Th1-dominated T-cell response and a balanced IgG2a/IgG1 ratio. Accordingly, the stretch of oligomannose glycans in the C2V3 domain of Env might mediate a specific uptake and/or signaling modus in antigen presenting cells by involving interaction with an as yet unknown C-type lectin receptor. Our results contribute to a deeper understanding of the impact of Env glycosylation on HIV antigen-specific immune responses, which will further support HIV vaccine development. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Review

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Open AccessReview
A Bioinformatics View of Glycan–Virus Interactions
Viruses 2019, 11(4), 374; https://doi.org/10.3390/v11040374
Received: 5 March 2019 / Revised: 5 April 2019 / Accepted: 15 April 2019 / Published: 23 April 2019
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Abstract
Evidence of the mediation of glycan molecules in the interaction between viruses and their hosts is accumulating and is now partially reflected in several online databases. Bioinformatics provides convenient and efficient means of searching, visualizing, comparing, and sometimes predicting, interactions in numerous and [...] Read more.
Evidence of the mediation of glycan molecules in the interaction between viruses and their hosts is accumulating and is now partially reflected in several online databases. Bioinformatics provides convenient and efficient means of searching, visualizing, comparing, and sometimes predicting, interactions in numerous and diverse molecular biology applications related to the -omics fields. As viromics is gaining momentum, bioinformatics support is increasingly needed. We propose a survey of the current resources for searching, visualizing, comparing, and possibly predicting host–virus interactions that integrate the presence and role of glycans. To the best of our knowledge, we have mapped the specialized and general-purpose databases with the appropriate focus. With an illustration of their potential usage, we also discuss the strong and weak points of the current bioinformatics landscape in the context of understanding viral infection and the immune response to it. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Other

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Open AccessMeeting Report
Glycans Controlling Virus Infections: Meeting Report on the 1st International Symposium on Glycovirology Schöntal, Germany, 02–04 May 2018
Viruses 2018, 10(11), 636; https://doi.org/10.3390/v10110636
Received: 11 November 2018 / Accepted: 12 November 2018 / Published: 15 November 2018
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Abstract
Glycans are, with nucleic acids, proteins and lipids, one of the four founding structures of cellular life. Due to their non-template synthesis, they are inherently heterogeneous and difficult to study with regards to their structure and function. Since 2016, the research group ViroCarb, [...] Read more.
Glycans are, with nucleic acids, proteins and lipids, one of the four founding structures of cellular life. Due to their non-template synthesis, they are inherently heterogeneous and difficult to study with regards to their structure and function. Since 2016, the research group ViroCarb, funded by the German Research Foundation, has investigated the role of glycans in non-enveloped virus infections with a highly interdisciplinary approach. The core idea was to bring together scientists and students from various disciplines such as structural biology, cell biology, virology and chemistry to advance research by an interdisciplinary means. In 2018, ViroCarb hosted the 1st International Symposium on Glycovirology in Schöntal, Germany, with a similar aim. Scientists from various disciplines gathered to discuss their area of study, present recent findings, establish or strengthen collaborations, and mentor the next generation of glycovirologists through formal presentations and informal discussions. The secluded meeting at the monastery of Schöntal gave ample time for in-depth discussions. On behalf of ViroCarb, this report summarizes the reports and highlights advances in the field. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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