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 Human Desmoglein-2 and Human CD46 Mediate Human Adenovirus Type 55 Infection, but Human Desmoglein-2 Plays the Major Roles

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Ying Feng ◽  
Changhua Yi ◽  
Xinglong Liu ◽  
Linbing Qu ◽  
Wan Su ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Gene Knockout ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Host Cells ◽  
Respiratory Pathogen ◽  
Cellular Receptors ◽  
Fiber Protein ◽  
Mouse Lines

ABSTRACT Human adenovirus type 55 (HAdV55) represents an emerging respiratory pathogen and causes severe pneumonia with high fatality in humans. The cellular receptors, which are essential for understanding the infection and pathogenesis of HAdV55, remain unclear. In this study, we found that HAdV55 binding and infection were sharply reduced by disrupting the interaction of viral fiber protein with human desmoglein-2 (hDSG2) but only slightly reduced by disrupting the interaction of viral fiber protein with human CD46 (hCD46). Loss-of-function studies using soluble receptors, blocking antibodies, RNA interference, and gene knockout demonstrated that hDSG2 predominantly mediated HAdV55 infection. Nonpermissive rodent cells became susceptible to HAdV55 infection when hDSG2 or hCD46 was expressed, but hDSG2 mediated more efficient HAd55 infection than hCD46. We generated two transgenic mouse lines that constitutively express either hDSG2 or hCD46. Although nontransgenic mice were resistant to HAdV55 infection, infection with HAdV55 was significantly increased in hDSG2+/+ mice but was much less increased in hCD46+/+ mice. Our findings demonstrate that both hDSG2 and hCD46 are able to mediate HAdV55 infection but hDSG2 plays the major roles. The hDSG2 transgenic mouse can be used as a rodent model for evaluation of HAdV55 vaccine and therapeutics. IMPORTANCE Human adenovirus type 55 (HAdV55) has recently emerged as a highly virulent respiratory pathogen and has been linked to severe and even fatal pneumonia in immunocompetent adults. However, the cellular receptors mediating the entry of HAdV55 into host cells remain unclear, which hinders the establishment of HAdV55-infected animal models and the development of antiviral approaches. In this study, we demonstrated that human desmoglein-2 (hDSG2) plays the major roles during HAdV55 infection. Human CD46 (hCD46) could also mediate the infection of HAdV55, but the efficiency was much lower than for hDSG2. We generated two transgenic mouse lines that express either hDSG2 or hCD46, both of which enabled HAd55 infection in otherwise nontransgenic mice. hDSG2 transgenic mice enabled more efficient HAdV55 infection than hCD46 transgenic mice. Our study adds to our understanding of HAdV55 infection and provides an animal model for evaluating HAdV55 vaccines and therapeutics.

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.

Infection and replication of human adenovirus type 3 possessing type 5 fiber protein in rodent cells

2020 ◽  
Vol 279 ◽  
pp. 197886
Author(s):  
Tiantian Liu ◽  
Mei Wang ◽  
Zhichao zhou ◽  
Ye Fan ◽  
Yun Xu ◽  
...  
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Fiber Protein ◽  
Type 3

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 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 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.

The penton base of human adenovirus type 3 has the RGD motif

Gene ◽  
1994 ◽  
Vol 146 (2) ◽  
pp. 257-259 ◽  
Author(s):  
Alain Cuzange ◽  
Jadwiga Chroboczek ◽  
Bernard Jacrot
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Penton Base ◽  
Rgd Motif ◽  
Type 3

scholarly journals Sequence of the human adenovirus type 3 protease

1988 ◽  
Vol 16 (23) ◽  
pp. 11374-11374 ◽  
Author(s):  
Alain Houde ◽  
Joseph M. Weber
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Type 3

Construction and characterization of a replication-competent human adenovirus type 3-based vector as a live-vaccine candidate and a viral delivery vector

Vaccine ◽  
2009 ◽  
Vol 27 (8) ◽  
pp. 1145-1153 ◽  
Author(s):  
Qiwei Zhang ◽  
Xiaobo Su ◽  
Donald Seto ◽  
Bo-jian Zheng ◽  
Xingui Tian ◽  
...  
Keyword(s):  
Vaccine Candidate ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Live Vaccine ◽  
Delivery Vector ◽  
Type 3
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