Department of Clinical Microbiology, Division of Virology, Umeå University, Umeå, Sweden.
Nat Med. 2011 Jan;17(1):105-9. doi: 10.1038/nm.2267. Epub 2010 Dec 12.
Adenovirus type 37 (Ad37) is a leading cause of epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular disease. Whereas most other adenoviruses infect cells by engaging CD46 or the coxsackie and adenovirus receptor (CAR), Ad37 binds previously unknown sialic acid-containing cell surface molecules. By glycan array screening, we show here that the receptor-recognizing knob domain of the Ad37 fiber protein specifically binds a branched hexasaccharide that is present in the GD1a ganglioside and that features two terminal sialic acids. Soluble GD1a glycan and GD1a-binding antibodies efficiently prevented Ad37 virions from binding and infecting corneal cells. Unexpectedly, the receptor is constituted by one or more glycoproteins containing the GD1a glycan motif rather than the ganglioside itself, as shown by binding, infection and flow cytometry experiments. Molecular modeling, nuclear magnetic resonance and X-ray crystallography reveal that the two terminal sialic acids dock into two of three previously established sialic acid-binding sites in the trimeric Ad37 knob. Surface plasmon resonance analysis shows that the knob-GD1a glycan interaction has high affinity. Our findings therefore form a basis for the design and development of sialic acid-containing antiviral drugs for topical treatment of EKC.
腺病毒 37 型（Ad37）是流行性角膜结膜炎（EKC）的主要病原体，EKC 是一种严重且具有高度传染性的眼部疾病。虽然大多数其他腺病毒通过结合 CD46 或柯萨奇病毒和腺病毒受体（CAR）来感染细胞，但 Ad37 结合以前未知的含有唾液酸的细胞表面分子。通过聚糖阵列筛选，我们在这里表明，Ad37 纤维蛋白的受体识别旋钮结构域特异性结合一种存在于 GD1a 神经节苷脂中的支化六糖，其特征是两个末端唾液酸。可溶性 GD1a 聚糖和与 GD1a 结合的抗体可有效阻止 Ad37 病毒颗粒结合和感染角膜细胞。出乎意料的是，受体由一个或多个含有 GD1a 聚糖基序的糖蛋白组成，而不是神经节苷脂本身，如结合、感染和流式细胞术实验所示。分子建模、核磁共振和 X 射线晶体学揭示了两个末端的唾液酸与三聚体 Ad37 旋钮中三个先前建立的唾液酸结合位点中的两个结合。表面等离子体共振分析表明，旋钮-GD1a 聚糖相互作用具有高亲和力。因此，我们的发现为设计和开发含有唾液酸的抗病毒药物提供了基础，用于 EKC 的局部治疗。
