Reduced influenza viral neutralizing activity of natural human trimers of surfactant protein D
Reduced influenza viral neutralizing activity of natural human trimers of surfactant protein D
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DOI：
10.1186/1465-9921-8-9
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发表时间：
2007-02-05
影响因子：
5.8
通讯作者：
Holmskov, Uffe
中科院分区：
文献类型：
--
作者：
Hartshorn, Kevan L.;White, Mitchell R.;Holmskov, Uffe
背景：表面活性蛋白D（SP-D）在宿主天然防御甲型流感病毒（IAV）感染中起重要作用。SP-D的常见人类多态性已在许多人群中发现，并与某些感染的风险增加有关。我们最近报道，Thr/Thr 11形式的SP-D与低血清水平和组装主要作为三聚体，而不是更常见的多聚体形式的SP-D。方法：进行初步实验，以建立不同的单克隆抗体对SP-D的能力，SP-D结合或中和病毒的影响。然后，我们从羊水中纯化天然人SP-D的三聚体和多聚体形式，并测试这些制剂结合IAV的能力，以抑制IAV在体外的感染性和血凝活性。结果：在最初的实验中，针对SP-D的CRD上的不同区域的mAb被发现具有不同的抗病毒活性的影响。使用不干扰SP-D抗病毒活性的mAb，我们证实天然SP-D三聚体与IAV结合的能力降低。此外，与天然人SP-D多聚体相比，三聚体具有降低的中和IAV的能力，以及降低的针对几种IAV菌株的血凝抑制活性。自然SP-D三聚体也有不同的相互作用与人类中性粒细胞肽防御素（HNP）在病毒中和试验相比，多聚体SP-D。结论：这些研究表明，一个共同的人类SP-D多态性形式可能会调节宿主防御IAV和推动临床研究相关的基因型与易感人群感染IAV的风险。我们还表明，针对SP-D的碳水化合物识别结构域上的不同区域的mAb可以用于解剖出蛋白质的不同功能特性。
Background: Surfactant protein D (SP-D) plays important roles in innate host defense against influenza A virus (IAV) infection. Common human polymorphisms of SP-D have been found in many human populations and associated with increased risk of certain infections. We recently reported that the Thr/Thr 11 form of SP-D is associated with low serum levels and assembles predominantly as trimers as opposed to the more common multimeric forms of SP-D.Methods: Preliminary experiments were done to establish the effects of different monoclonal antibodies against SP-D on ability of SP-D to bind to or neutralize the virus. We then purified natural human trimeric and multimeric forms of SP-D from amniotic fluid and tested ability of these preparations to bind to IAV, to inhibit infectivity and hemagglutination activity of IAV in vitro.Results: In initial experiments mAbs directed against different areas on the CRD of SP-D were found to have differing effects on antiviral activity. Using an mAb that did not interfere with antiviral activity of SP-D, we confirm that natural SP-D trimers had reduced ability to bind to IAV. In addition, the trimers had reduced ability to neutralize IAV as compared to natural human SP-D multimers as well as reduced hemagglutination inhibiting activity against several strains of IAV. Natural SP-D trimers also had different interactions with human neutrophil peptide defensins (HNPs) in viral neutralization assays as compared to multimeric SP-D.Conclusion: These studies indicate that a common human polymorphic form of SP-D may modulate host defense against IAV and give impetus to clinical studies correlating this genotype with risk for IAV infection in susceptible groups. We also show that mAbs directed against different areas on the carbohydrate recognition domain of SP-D can be useful for dissecting out different functional properties of the protein.