Section of Virology, Department of Clinical Microbiology, Umeå University, SE-90185 Umeå, Sweden.
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Viruses. 2019 Apr 27;11(5):395. doi: 10.3390/v11050395.
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.
人类腺病毒（HAdV）是眼部感染最常见的原因。B 型人类腺病毒 3 型（HAdV-B3）引起咽结膜热（PCF），而 HAdV-D8、-D37 和 -D64 引起流行性角膜结膜炎（EKC）。最近，HAdV-D53、-D54 和 -D56 成为新的 EKC 致病因子。HAdV-E4 与 PCF 和 EKC 都有关。我们之前已经证明 HAdV-D37 在人角膜上皮（HCE）细胞上使用含唾液酸（SA）的聚糖作为细胞受体，病毒与 SA 的相互作用由病毒纤维蛋白的球状结构域介导。在这里，我们通过细胞测定并使用神经氨酸酶（一种 SA 切割酶），研究了除 HAdV-D37 以外的眼部 HAdV 是否也将含 SA 的聚糖作为 HCE 细胞上的受体。我们发现 HAdV-E4 和 -D56 独立于 SA 感染 HCE 细胞，而 HAdV-D53 和 -D64 使用 SA 作为细胞受体。HAdV-D8 和 -D54 纤维球状结构域也与细胞表面的 SA 结合。令人惊讶的是，我们发现 HCE 细胞对 HAdV-B3 感染具有抗性。我们还证明，基于 SA 的分子 ME0462 设计用于与 HAdV-D37 纤维球状结构域上的 SA 结合位点结合，可有效阻止几种 EKC 致病 HAdV 的结合和感染。表面等离子体共振分析证实 ME0462 与纤维球状结构域之间存在直接相互作用。总之，我们证明含 SA 的聚糖是多种 EKC 致病 HAdV 的受体，基于 SA 的化合物可作为针对已知和新出现的 EKC 致病 HAdV 的广谱抗病毒药物。
