Plos Pathogens:高福院士课题组揭示D型流感病毒入侵机制

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流感病毒是重要的病原体之一，不仅严重威胁人类健康，而且给畜牧业生产造成重大损失。之前流感病毒一直分为A、B和C三个类型，从2011年起科学家陆续在猪和牛体内分离到新的流感病毒，由于此新病毒与A、B、C型流感病毒差异很大，被定义为新的D型流感病毒。新发现的D型流感病毒与C型流感病毒最为相似，但不能与C型流感病毒发生重组。目前已在北美、欧洲、中国等多个国家和地区检测到此新型流感病毒，牛被认为是主要宿主。D型流感病毒比C型流感病毒存在更广谱的细胞嗜性，能够感染牛、猪、雪貂和豚鼠并通过接触传播感染其它动物，有报道称在小反刍动物如绵羊和山羊体内等也存在针对D型流感病毒的特异性抗体。

因此，D型流感病毒的入侵分子机制成为世界科学家所关注的焦点，中国科学院微生物研究所高福研究团队在该研究中取得新进展，相关研究成果已于1月27日在线发表在病毒学杂志PLoS Pathogens 上。

研究人员利用结构生物学手段及功能实验研究了D型流感病毒表面唯一的糖蛋白HEF，通过糖点阵芯片实验证明了D型流感病毒能结合9-O乙酰唾液酸受体及其多种衍生物。随后，研究人员解析了D型流感病毒HEF蛋白及其与不同受体类似物的复合物结构，他们发现D型流感病毒HEF的受体结合位点的230-helix和270-loop存在一个开放的通道，而在C型流感病毒HEF相同的位置，230-helix的K235和270-loop的D269形成盐桥相互作用，将270-loop拉高与230-helix相连，关闭了通道（图1）。D型流感病毒HEF蛋白受体结合位点的开放通道使得D型流感病毒能够容纳不同的糖环构象，从而结合9-O乙酰唾液酸受体及其不同衍生物，为其广泛的细胞嗜性提供了结构基础。组织免疫荧光实验表明D型流感病毒HEF能结合人、猪和牛的气管纤毛上皮细胞。考虑到D型流感病毒不仅能够导致牛和猪发病，而且能够在雪貂和豚鼠中传播，必须警惕和防范其对公共安全的威胁。

微生物所高福课题组的博士宋豪为文章的第一作者，高福为通讯作者。研究得到国家科技部“973”项目、自然科学基金委项目和中科院项目等资助。

来源：微生物研究所

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An Open Receptor-Binding Cavity of Hemagglutinin-Esterase-Fusion Glycoprotein from Newly-Identified Influenza D Virus: Basis for Its Broad Cell Tropism

Hao Song, Jianxun Qi, Zahra Khedri, Sandra Diaz, Hai Yu, Xi Chen, Ajit Varki, Yi Shi, George F. Gao

Abstract
Influenza viruses cause seasonal flu each year and pandemics or epidemic sporadically, posing a major threat to public health. Recently, a new influenza D virus (IDV) was isolated from pigs and cattle. Here, we reveal that the IDV utilizes 9-O-acetylated sialic acids as its receptor for virus entry. Then, we determined the crystal structures of hemagglutinin-esterase-fusion glycoprotein (HEF) of IDV both in its free form and in complex with the receptor and enzymatic substrate analogs. The IDV HEF shows an extremely similar structural fold as the human-infecting influenza C virus (ICV) HEF. However, IDV HEF has an open receptor-binding cavity to accommodate diverse extended glycan moieties. This structural difference provides an explanation for the phenomenon that the IDV has a broad cell tropism. As IDV HEF is structurally and functionally similar to ICV HEF, our findings highlight the potential threat of the virus to public health.

Author Summary
Of the Orthomyxoviridae family of viruses, influenza A, B and C viruses all can cause disease in humans. Recently, a novel influenza D virus (IDV) with approximately 50% amino acid identity to human influenza C virus (ICV) is found in pigs and cattle. This novel virus can establish infection in other mammals including ferrets and guinea pigs. However, the cellular receptor for viral entry and the molecular mechanism for its broad host range is unclear. We performed combined structural and functional studies on the viral surface protein, hemagglutinin-esterase-fusion (HEF), and demonstrated that IDV (like ICV) uses 9-O-acetylated sialic acid as its receptor, but the IDV HEF has an open receptor-binding cavity to accommodate diverse extended glycan moieties. Our findings reveal in exquisite detail how the receptors or substrates bind to the receptor-binding site or esterase active site, providing a clue for the development of novel therapeutics against the conserved esterase pocket. Furthermore, the IDV HEF can bind human trachea epithelia, indicating that the IDV virus may become a potential threat to public health.

http://journals.plos.org/plospat ... ournal.ppat.1005411