scholarly journals Human adenovirus type 26 uses sialic acid–bearing glycans as a primary cell entry receptor

2019 ◽  
Vol 5 (9) ◽  
pp. eaax3567 ◽  
Author(s):  
Alexander T. Baker ◽  
Rosie M. Mundy ◽  
James A. Davies ◽  
Pierre J. Rizkallah ◽  
Alan L. Parker
Keyword(s):  
Sialic Acid ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Receptor ◽  
Primary Cell ◽  
Virus Infections ◽  
Epidemic Keratoconjunctivitis ◽  
Dna Viruses ◽  
Syncytial Virus ◽  
Entry Receptor

Adenoviruses are clinically important agents. They cause respiratory distress, gastroenteritis, and epidemic keratoconjunctivitis. As non-enveloped, double-stranded DNA viruses, they are easily manipulated, making them popular vectors for therapeutic applications, including vaccines. Species D adenovirus type 26 (HAdV-D26) is both a cause of EKC and other diseases and a promising vaccine vector. HAdV-D26–derived vaccines are under investigation as protective platforms against HIV, Zika, and respiratory syncytial virus infections and are in phase 3 clinical trials for Ebola. We recently demonstrated that HAdV-D26 does not use CD46 or Desmoglein-2 as entry receptors, while the putative interaction with coxsackie and adenovirus receptor is low affinity and unlikely to represent the primary cell receptor. Here, we establish sialic acid as a primary entry receptor used by HAdV-D26. We demonstrate that removal of cell surface sialic acid inhibits HAdV-D26 infection, and provide a high-resolution crystal structure of HAdV-D26 fiber-knob in complex with sialic acid.

scholarly journals Adenovirus serotype 26 utilises sialic acid bearing glycans as a primary cell entry receptor

2019 ◽  
Author(s):  
Alexander T. Baker ◽  
Rosie Mundy ◽  
James Davies ◽  
Pierre J. Rizkallah ◽  
Alan L Parker
Keyword(s):  
Sialic Acid ◽  
Cell Receptor ◽  
Primary Cell ◽  
Phase Iii ◽  
Epidemic Keratoconjunctivitis ◽  
Adenovirus Serotype ◽  
Dna Viruses ◽  
Phase Iii Clinical Trials ◽  
Adenovirus Receptor ◽  
Entry Receptor

AbstractAdenoviruses are clinically important agents. They cause respiratory distress, gastroenteritis, and epidemic keratoconjunctivitis (EKC). As non-enveloped, double stranded DNA viruses, they are easily manipulated, making them popular vectors for therapeutic applications, including vaccines. Species D adenovirus serotype 26 (HAdV-D26) is both a cause of EKC and other disease, and a promising vaccine vector. HAdV-D26 derived vaccines are under investigation as protective platforms against HIV, Zika, RSV infections and are in Phase-III clinical trials for Ebola.We recently demonstrated that HAdV-D26 does not utilise CD46 or desmoglein 2 as entry receptors, whilst the putative interaction with Coxsackie and Adenovirus Receptor (CAR) is low affinity and unlikely to represent the primary cell receptor.Here, we definitively establish sialic acid as the primary entry receptor utilised by HAdV-D26. We demonstrate removal of cell surface sialic acid inhibits HAdV-D26 infection and provide a high-resolution crystal structure of HAdV-D26 fiber-knob in complex with sialic acid.

scholarly journals Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and Treatment

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 395 ◽  
Author(s):  
Naresh Chandra ◽  
Lars Frängsmyr ◽  
Sophie Imhof ◽  
Rémi Caraballo ◽  
Mikael Elofsson ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Direct Interaction ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Epidemic Keratoconjunctivitis ◽  
Surface Plasmon Resonance Analysis ◽  
Cellular Receptors ◽  
Human Adenoviruses ◽  
Fiber Protein ◽  
Type 3

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.

scholarly journals Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37 – Viruses That Cause Highly Contagious Eye Infections

2020 ◽  
Author(s):  
Emil Johansson ◽  
Rémi Caraballo ◽  
Nitesh Mistry ◽  
Georg Zocher ◽  
Weixing Qian ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Antiviral Agents ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Inhibitory Effect ◽  
Host Cells ◽  
Epidemic Keratoconjunctivitis ◽  
Coxsackievirus A24 Variant ◽  
Causative Agents ◽  
Coxsackievirus A24

Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection, and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.

scholarly journals Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37 – Viruses That Cause Highly Contagious Eye Infections

2020 ◽  
Author(s):  
Emil Johansson ◽  
Rémi Caraballo ◽  
Nitesh Mistry ◽  
Georg Zocher ◽  
Weixing Qian ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Antiviral Agents ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Inhibitory Effect ◽  
Host Cells ◽  
Epidemic Keratoconjunctivitis ◽  
Coxsackievirus A24 Variant ◽  
Causative Agents ◽  
Coxsackievirus A24

Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection, and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.

scholarly journals Decoy Receptor Interactions as Novel Drug Targets against EKC-Causing Human Adenovirus

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 242 ◽  
Author(s):  
Naresh Chandra ◽  
Lars Frängsmyr ◽  
Niklas Arnberg
Keyword(s):  
Drug Targets ◽  
Antiviral Drug ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Antiviral Effect ◽  
Epidemic Keratoconjunctivitis ◽  
Virus Binding ◽  
Decoy Receptor ◽  
Decoy Receptors ◽  
Approved Drugs

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.

scholarly journals Notes from the Field: Epidemic Keratoconjunctivitis Outbreak Associated with Human Adenovirus Type 8 — U.S. Virgin Islands, June–November 2016

2017 ◽  
Vol 66 (30) ◽  
pp. 811-812 ◽  
Author(s):  
Marie E. Killerby, ◽  
Matthew J. Stuckey, ◽  
Irene Guendel, ◽  
Senthilkumar Sakthivel, ◽  
Xiaoyan Lu, ◽  
...  
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Virgin Islands ◽  
Epidemic Keratoconjunctivitis

scholarly journals Five Cases of Epidemic Keratoconjunctivitis Due to Human Adenovirus Type 85 in Fukushima, Japan

2020 ◽  
Vol 73 (4) ◽  
pp. 316-319
Author(s):  
Hisatoshi Kaneko ◽  
Nozomu Hanaoka ◽  
Masami Konagaya ◽  
Masaaki Kobayashi ◽  
Hisashi Nakagawa ◽  
...  
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Epidemic Keratoconjunctivitis

scholarly journals Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37–Viruses That Cause Highly Contagious Eye Infections

2020 ◽  
Vol 15 (10) ◽  
pp. 2683-2691
Author(s):  
Emil Johansson ◽  
Rémi Caraballo ◽  
Nitesh Mistry ◽  
Georg Zocher ◽  
Weixing Qian ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Eye Infections ◽  
Coxsackievirus A24 Variant ◽  
Coxsackievirus A24
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