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Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and
Naresh Chandra1, Lars Frängsmyr2, Sophie Imhof3
1Section of Virology, Department of Clinical Microbiology, Umeå University, SE-90185 Umeå, Sweden. naresh.chandra@umu.se.
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 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.
Insights
Human adenoviruses causing eye infections utilize sialic acid (SA) receptors on corneal cells. A novel SA-based compound effectively blocks multiple epidemic keratoconjunctivitis (EKC)-causing adenoviruses, offering broad-spectrum protection.
Area of Science:
- Ophthalmology
- Virology
- Cell Biology
Background:
- Human adenoviruses (HAdV) are a leading cause of ocular infections, including epidemic keratoconjunctivitis (EKC) and pharyngoconjunctival fever (PCF).
- Previous research identified sialic acid (SA)-containing glycans as receptors for HAdV-D37 on human corneal epithelial (HCE) cells, mediated by the viral fiber knob protein.
Purpose of the Study:
- To investigate if other ocular HAdVs, particularly EKC-causing types, also use SA-containing glycans as cellular receptors on HCE cells.
- To evaluate the potential of SA-based molecules as broad-spectrum antivirals against EKC-causing HAdVs.
Main Methods:
- Cell-based infection assays using HCE cells treated with neuraminidase (an SA-cleaving enzyme).
- Analysis of HAdV fiber knob binding to cell-surface SAs using surface plasmon resonance.
- Testing the efficacy of an SA-based molecule (ME0462) against HAdV binding and infection.
Main Results:
- HAdV-E4 and HAdV-D56 infection of HCE cells occurred independently of SA.
- HAdV-D53 and HAdV-D64 utilized SA as cellular receptors.
- HAdV-D8 and HAdV-D54 fiber knobs bound to cell-surface SAs, while HAdV-B3 was resistant to HCE cell infection.
- The SA-based molecule ME0462 demonstrated broad-spectrum antiviral activity, preventing binding and infection by multiple EKC-causing HAdVs.
Conclusions:
- Sialic acid-containing glycans serve as critical cellular receptors for a range of epidemic keratoconjunctivitis (EKC)-causing human adenoviruses.
- SA-based compounds, such as ME0462, represent a promising therapeutic strategy for a broad spectrum of ocular adenovirus infections, including emerging strains.
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