A Recombinant Sialidase Fusion Protein Effectively Inhibits Human Parainfluenza Viral Infection In Vitro and In Vivo
A Recombinant Sialidase Fusion Protein Effectively Inhibits Human Parainfluenza Viral Infection In Vitro and In Vivo
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DOI：
10.1086/653621
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发表时间：
2010-07-15
影响因子：
6.4
通讯作者：
Fang, Fang
中科院分区：
文献类型：
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作者：
Moscona, Anne;Porotto, Matteo;Fang, Fang
背景资料。人类副流感病毒(HPIV)感染的第一步是通过病毒受体结合分子和含唾液酸受体的相互作用与呼吸道上皮细胞表面结合。DAS181是一种含有粘性放线菌唾液酸酶催化结构域的重组唾液酸酶蛋白，它可以去除细胞表面的唾液酸，我们认为它可以抑制HPIV感染。用凝集素结合实验评价DAS181对唾液酸受体的耗竭作用。通过病毒基因组和/或空斑形成单位的减少来评估培养的细胞系和人的呼吸道上皮中的抗HPIV活性。用棉鼠模型评价DAS181鼻腔给药的体内疗效。DAS181介导的去滴定能在细胞系和人呼吸道上皮细胞中诱导抗HPIV活性。大鼠鼻腔注射DAS181作为人类疾病模型，可显著减少感染。酶去除HPIV受体的唾液酸部分可以抑制所有被测试的HPIV毒株的感染，无论是在体外还是在棉鼠体内。酶介导的唾液酸受体去除代表了HPIV的一种新的抗病毒策略。这项研究的结果增加了开发广谱抗病毒药物治疗流感病毒和HPIV的可能性。
Background. The first step in infection by human parainfluenza viruses (HPIVs) is binding to the surface of respiratory epithelial cells via interaction between viral receptor-binding molecules and sialic acid-containing receptors. DAS181, a recombinant sialidase protein containing the catalytic domain of Actinomyces viscosus sialidase, removes cell surface sialic acid, and we proposed that it would inhibit HPIV infection.Methods. Depletion of sialic acid receptors by DAS181 was evaluated by lectin-binding assays. Anti-HPIV activity in cultured cell lines and in human airway epithelium was assessed by the reduction in viral genomes and/or plaque forming units on treatment. In vivo efficacy of intranasally administered DAS181 was assessed using a cotton rat model.Results. DAS181-mediated desialylation led to anti-HPIV activity in cell lines and human airway epithelium. Intranasal DAS181 in cotton rats, a model for human disease, significantly curtailed infection.Conclusions. Enzymatic removal of the sialic acid moiety of HPIV receptors inhibits infection with all tested HPIV strains, both in vitro and in cotton rats. Enzyme-mediated removal of sialic acid receptors represents a novel antiviral strategy for HPIV. The results of this study raise the possibility of a broad spectrum antiviral agent for influenza virus and HPIVs.