scholarly journals Sulfated Glycosaminoglycans as Viral Decoy Receptors for Human Adenovirus Type 37

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 247 ◽  
Author(s):  
Naresh Chandra ◽  
Yan Liu ◽  
Jing-Xia Liu ◽  
Lars Frängsmyr ◽  
Nian Wu ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Therapeutic Potential ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Sodium Chlorate ◽  
Target Cells ◽  
Epidemic Keratoconjunctivitis ◽  
Virus Binding ◽  
Surface Plasmon Resonance Analysis ◽  
Decoy Receptors

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.

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 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 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 Analysis of the complete genome sequence of epidemic keratoconjunctivitis-related human adenovirus type 8, 19, 37 and a novel serotype

2009 ◽  
Vol 90 (6) ◽  
pp. 1471-1476 ◽  
Author(s):  
Hisatoshi Kaneko ◽  
Tomohiro Iida ◽  
Hiroaki Ishiko ◽  
Takeshi Ohguchi ◽  
Toshihide Ariga ◽  
...  
Keyword(s):  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Clinical Strain ◽  
Epidemic Keratoconjunctivitis ◽  
Hypervariable Regions ◽  
Distinct Cluster ◽  
Loop 2

We determined the complete genome sequence of epidemic keratoconjunctivitis (EKC)-related human adenoviruses (HAdVs). We analysed a total of 12 HAdV strains; three prototype strains and two HAdV-8, three HAdV-19 and three HAdV-37 clinical isolates from EKC patients in Japan, and one novel serotype of HAdV. Genome organization of these serotypes was identical to those of the recently determined HAdV-19 and HAdV-37. The identities of the whole genome were over 99 % among strains from the same serotype, except for HAdV-19p, which is not associated with conjunctivitis, resulting in the formation of a distinct cluster in the phylogenetic analysis. The penton, loop 1 and loop 2 of hexon, early region 3 (E3) and fiber were hypervariable regions between serotypes. Results suggest that the HAdV-19 clinical strain is a recombinant of HAdV-19p-like and HAdV-37-like strains, and that the acquisition of the penton, E3 or fiber may be related to ocular tropism.

scholarly journals Recombination analysis of intermediate human adenovirus type 53 in Japan by complete genome sequence

2011 ◽  
Vol 92 (6) ◽  
pp. 1251-1259 ◽  
Author(s):  
Hisatoshi Kaneko ◽  
Koki Aoki ◽  
Susumu Ishida ◽  
Shigeaki Ohno ◽  
Nobuyoshi Kitaichi ◽  
...  
Keyword(s):  
Complete Genome ◽  
Phylogenetic Analyses ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Penton Base ◽  
Recombination Detection Program ◽  
Genome Sequences ◽  
Epidemic Keratoconjunctivitis ◽  
Detection Program ◽  
Recombination Breakpoints

Human adenovirus type 53 (HAdV-53) has commonly been detected in samples from epidemic keratoconjunctivitis (EKC) patients in Japan since 1996. HAdV-53 is an intermediate virus, containing hexon-chimeric, penton base and fiber structures similar to HAdV-22 and -37, HAdV-37 and HAdV-8, respectively. HAdV-53-like intermediate strains were first isolated from EKC samples in Japan in the 1980s. Here, the complete genome sequences of three such HAdV-53-like intermediate strains (870006C, 880249C and 890357C) and four HAdV-53 strains were determined, and their relationships were analysed. The seven HAdV strains were classified into three groups, 870006C/880249C, 890357C and the four HAdV-53 strains, on the basis of phylogenetic analyses of the partial and complete genome sequences. HAdV strains within the same group showed the highest nucleotide identities (99.87–100.00 %). Like HAdV-53, the hexon loop 1 and 2 regions of 870006C, 880249C and 890357C showed the highest identity with HAdV-22. However, these strains did not show a hexon-chimeric structure similar to HAdV-22 and -37, or a penton base similar to HAdV-37. The fiber genes of 870006C and 880249C were identical to that of HAdV-37, but not HAdV-8. Thus, the three intermediate HAdVs isolated in the 1980s were similar to each other but not to HAdV-53. The recombination breakpoints were inferred by the Recombination Detection Program (rdp) using whole-genome sequences of these seven HAdV and of 12 HAdV-D strains from GenBank. HAdV-53 may have evolved from intermediate HAdVs circulating in the 1980s, and from HAdV-8, -22 and -37, by recombination of sections cut at the putative breakpoints.

scholarly journals Outbreak of Epidemic Keratoconjunctivitis Caused by Human Adenovirus Type 56, China, 2012

PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e110781 ◽  
Author(s):  
Guohong Huang ◽  
Wenqing Yao ◽  
Wei Yu ◽  
Lingling Mao ◽  
Haibo Sun ◽  
...  
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Epidemic Keratoconjunctivitis
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