College of Veterinary Medicine, China Agricultural University, Beijing, China.
J Virol. 2013 Aug;87(16):9077-85. doi: 10.1128/JVI.00235-13. Epub 2013 Jun 12.
Interspecies transmission (host switching/jumping) of influenza viruses is a key scientific question that must be addressed. In addition to the vigorous research on highly pathogenic avian influenza viruses (HPAIVs), studies of the mechanism of interspecies transmission of low-pathogenic avian influenza viruses (LPAIVs) could also provide insights into host tropism and virulence evolution. Influenza A viruses harboring hemagglutinin (HA) H13 (e.g., H13N6) are LPAIVs. In this study, soluble H13 HA glycoprotein was purified, and its receptor binding activity was characterized. The results revealed that H13 exclusively binds the avian α2-3-linked sialic acid receptor; no binding to the mammalian α2-6-linked sialic acid receptor was detected. Furthermore, the molecular basis of the H13 receptor binding specificity was revealed by comparative analysis of the crystal structures of both receptor-bound H13 and H5 HAs, which might be contributed by the hydrophobic residue V186. Work with an H13N186 mutant confirmed the importance of V186 in the receptor binding specificity of H13 HA, which shows that the mutant protein reduced the binding of an avian receptor analog but increased the binding of a human receptor analog. Detailed structural analysis also demonstrated that the conserved binding sites of the recently well-studied broadly neutralizing human monoclonal antibodies targeting the HA2 domain are found in H13. Our results expand our understanding of virulence evolution, receptor binding preference, and species tropism of the LPAIVs and HPAIVs.
流感病毒的种间传播（宿主转换/跳跃）是一个必须解决的关键科学问题。除了对高致病性禽流感病毒（HPAIVs）的大力研究外，对低致病性禽流感病毒（LPAIVs）种间传播机制的研究也可以深入了解宿主嗜性和毒力进化。携带血凝素（HA）H13（例如 H13N6）的甲型流感病毒是 LPAIVs。在这项研究中，纯化了可溶性 H13 HA 糖蛋白，并对其受体结合活性进行了表征。结果表明，H13 仅结合禽α2-3 连接的唾液酸受体；未检测到与哺乳动物α2-6 连接的唾液酸受体结合。此外，通过比较受体结合的 H13 和 H5 HAs 的晶体结构，揭示了 H13 受体结合特异性的分子基础，这可能归因于疏水残基 V186。对 H13N186 突变体的研究证实了 V186 在 H13 HA 受体结合特异性中的重要性，表明突变蛋白降低了禽受体类似物的结合，但增加了人受体类似物的结合。详细的结构分析还表明，最近广泛研究的针对 HA2 结构域的广谱中和人单克隆抗体的保守结合位点存在于 H13 中。我们的研究结果扩展了我们对 LPAIVs 和 HPAIVs 的毒力进化、受体结合偏好和物种嗜性的理解。
