Viral Evasion of Innate Immune Defense: The Case of Resistance of Pandemic H1N1 Influenza A Virus to Human Mannose-Binding Proteins.
Viral Evasion of Innate Immune Defense: The Case of Resistance of Pandemic H1N1 Influenza A Virus to Human Mannose-Binding Proteins.
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DOI：
10.3389/fmicb.2021.774711
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发表时间：
2021
影响因子：
5.2
通讯作者：
Hartshorn KL
中科院分区：
文献类型：
--
作者：
White MR;Nikolaidis NM;McCormack F;Crouch EC;Hartshorn KL
甘露糖结合凝集素有效地抑制大多数季节性甲型流感病毒株，并有助于针对这些病毒的天然宿主防御。相比之下，大流行性IAV毒株在很大程度上对这些凝集素具有抗药性，可能导致更大的传播和更糟糕的结果。在这篇文章中，我们评估了人、细菌和真菌来源的甘露糖结合凝集素对IAV的抑制作用，以了解并可能增加对大流行IAV的活性。在目前的研究中，具有325和343位组合取代的人表面活性蛋白D(SP-D)Neck和碳水化合物识别结构域(NCRD)的修饰版本，先前已被证明在体外和体内抑制大流行H3N2IAV，并在体外抑制大流行H1N1，但未能在体内保护小鼠免受大流行H1N1的影响。我们尝试了各种策略来提高突变型NCRD对2009年大流行H1N1的活性，包括形成包含突变型NCRD的全长SP-D分子，通过使用抗体使NCRD交联，将SP-D或NCRD与α-2-巨球蛋白结合，以及在双突变NCRD中引入额外的突变。所有这些都没有显著增加甲型H1N1流感大流行的抗病毒活性。我们还测试了细菌和藻类甘露糖结合凝集素、氰化韦林和格里菲辛对IAV的活性。这些药物对季节性IAV有很强的活性，而季节性IAV在很大程度上保留了对大流行H1N1的作用。我们提出了一些机制来解释SP-D构建体对大流行H3N2和H1N1的活性差异，以及氰病毒素与SP-D构建体活性的差异。
Mannose-binding lectins effectively inhibit most seasonal strains of influenza A virus and contribute to the innate host defense vs. these viruses. In contrast, pandemic IAV strains are largely resistant to these lectins, likely contributing to increased spread and worse outcomes. In this paper, we evaluated the inhibition of IAV by mannose-binding lectins of human, bacterial, and fungal origin to understand and possibly increase activity vs. the pandemic IAV. A modified version of the human surfactant protein D (SP-D) neck and carbohydrate recognition domain (NCRD) with combinatorial substitutions at the 325 and 343 positions, previously shown to inhibit pandemic H3N2 IAV in vitro and in vivo, and to inhibit pandemic H1N1 in vitro, failed to protect mice from pandemic H1N1 in vivo in the current study. We attempted a variety of maneuvers to improve the activity of the mutant NCRDs vs. the 2009 pandemic H1N1, including the formation of full-length SP-D molecules containing the mutant NCRD, cross-linking of NCRDs through the use of antibodies, combining SP-D or NCRDs with alpha-2-macroglobulin, and introducing an additional mutation to the double mutant NCRD. None of these substantially increased the antiviral activity for the pandemic H1N1. We also tested the activity of bacterial and algal mannose-binding lectins, cyanovirin, and griffithsin, against IAV. These had strong activity against seasonal IAV, which was largely retained against pandemic H1N1. We propose mechanisms to account for differences in activity of SP-D constructs against pandemic H3N2 and H1N1, and for differences in activity of cyanovirin vs. SP-D constructs.
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