Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi, USA.
Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi, USA.
J Virol. 2018 Aug 29;92(18). doi: 10.1128/JVI.01115-18. Print 2018 Sep 15.
An outbreak of respiratory disease caused by the equine-origin influenza A(H3N8) virus was first detected in dogs in 2004 and since then has been enzootic among dogs. Currently, the molecular mechanisms underlying host adaption of this virus from horses to dogs is unknown. Here, we have applied quantitative binding, growth kinetics, and immunofluorescence analyses to elucidate these mechanisms. Our findings suggest that a substitution of W222L in the hemagglutinin of the equine-origin A(H3N8) virus facilitated its host adaption to dogs. This mutation increased binding avidity of the virus specifically to receptor glycans with -glycolylneuraminic acid (Neu5Gc) and sialyl Lewis X (SLe) motifs. We have demonstrated these motifs are abundantly located in the submucosal glands of dog trachea. Our findings also suggest that in addition to the type of glycosidic linkage (e.g., α2,3-linkage or α2,6-linkage), the type of sialic acid (Neu5Gc or 5--acetyl neuraminic acid) and the glycan substructure (e.g., SLe) also play an important role in host tropism of influenza A viruses. Influenza A viruses (IAVs) cause a significant burden on human and animal health, and mechanisms for interspecies transmission of IAVs are far from being understood. Findings from this study suggest that an equine-origin A(H3N8) IAV with mutation W222L at its hemagglutinin increased binding to canine-specific receptors with sialyl Lewis X and Neu5Gc motifs and, thereby, may have facilitated viral adaption from horses to dogs. These findings suggest that in addition to the glycosidic linkage (e.g., α2,3-linked and α2,6-linked), the substructure in the receptor saccharides (e.g., sialyl Lewis X and Neu5Gc) could present an interspecies transmission barrier for IAVs and drive viral mutations to overcome such barriers.
2004 年，首次在犬中检测到由马源甲型流感病毒 A(H3N8)引起的呼吸道疾病爆发，此后该病毒在犬中持续流行。目前，这种病毒从马传播到犬的宿主适应的分子机制尚不清楚。在这里，我们应用定量结合、生长动力学和免疫荧光分析来阐明这些机制。我们的研究结果表明，马源 A(H3N8)病毒血凝素中 W222L 的取代促进了其对犬的宿主适应性。这种突变增加了病毒对含有 - 甘油神经氨酸（Neu5Gc）和唾液酸 Lewis X（SLe）基序的受体糖蛋白的结合亲和力。我们已经证明这些基序在狗气管的粘膜下腺中大量存在。我们的研究结果还表明，除了糖苷键类型（例如，α2,3-键或α2,6-键）外，唾液酸的类型（Neu5Gc 或 5-乙酰神经氨酸）和聚糖亚结构（例如 SLe）也在流感病毒的宿主嗜性中发挥重要作用。流感病毒（IAVs）对人类和动物健康造成重大负担，IAVs 的种间传播机制远未被理解。本研究的结果表明，具有血凝素 W222L 突变的马源 A(H3N8)IAV 增加了与犬特异性带有 SLe 和 Neu5Gc 基序的受体的结合，从而可能促进了病毒从马传播到犬。这些发现表明，除了糖苷键（例如，α2,3-连接和α2,6-连接）外，受体糖中的亚结构（例如，唾液酸 Lewis X 和 Neu5Gc）可能是 IAV 种间传播的障碍，并促使病毒发生突变以克服这些障碍。
