Influenza D Virus Entry and Tissue Tropism

项目摘要 新型D型流感病毒（IDV）利用牛作为周期性溢出的主要宿主， 其他哺乳动物宿主，包括猪和马。更重要的公共卫生，血清学 IDV在人类中感染的证据已经得到证实。初步调查显示 IDV结合人9-O-乙酰化N-乙酰神经氨酸（Neu5，9Ac2），人的受体 C型流感病毒（ICV）和非人N-羟乙酰神经氨酸（Neu5Gc9Ac），并可能利用 病毒进入。进一步的功能研究表明，IDV在识别这两个方面更有效 人Neu5，9Ac 2-和非人Neu5Gc9Ac-含聚糖的浓度高于ICV，ICV似乎 相对于非人Neu5Gc9Ac，其优先结合人Neu5，9Ac 2。为此，ICV 宿主范围有限，人类是宿主。这些结果表明，IDV和ICV的分歧， 与唾液酸（SA）沟通以进行感染。假设是， 位于血凝素-酯酶-融合物中的受体结合口袋的序列和结构 (HEF)IDV和ICV之间的蛋白质引起病毒-受体相互作用的实质性差异， 其可以扩张或缩小，或改变组织和物种向性。此外，最近 观察IDV对低pH灭活的细胞外抗性与细胞内抗性， 病毒进入所需的低pH值提示了一种新的进入/融合机制， 将其基因组导入靶细胞。本文提出了三个目标来解决这些假设。 R01应用，其中涉及IDV和ICV的比较研究。目标1将阐明条目 目的2将定义HEF受体结合亲和力的分子基础， 特异性及其对IDV向性的影响。目的3是为了解决两个IDV谱系，猪和 牛，阅读聚糖受体的差异，以及如何将这些信息转导到不同的 这两组IDV之间的组织和物种向性。总而言之，本提案利用了 团队在IDV研究和IDV-受体相互作用的新方面的专业知识， IDV的跨物种传播机制。了解病毒受体的分子细节 这种相互作用可能导致开发新的策略来控制和预防IDV和ICV 人类感染。

PROJECT SUMMARY Novel influenza D virus (IDV) utilizes bovines as a primary reservoir with periodical spillover to other mammalian hosts including pigs and horses. Of greater public health importance, serological evidence of IDV infections in humans has been demonstrated. Preliminary investigations have revealed that IDV binds to human 9-O-acetylated N-acetylneuraminic acid (Neu5,9Ac2), the receptor of human influenza C virus (ICV), and non-human N-glycolylneuraminic acid (Neu5Gc9Ac) and likely utilizes them for viral entry. Further functional studies indicate that IDV is more efficient in recognizing both human Neu5,9Ac2- and non-human Neu5Gc9Ac-containing glycans than ICV, and ICV seems to preferentially bind to human Neu5,9Ac2 over non-human Neu5Gc9Ac. In agreement with this, ICV has a limited host range with humans as a reservoir. These results suggest that IDV and ICV diverge in communicating with sialic acids (SA) for infection. The hypothesis is that subtle differences in the sequence and structure of the receptor-binding pocket residing in the hemagglutinin-esterase-fusion (HEF) protein between IDV and ICV cause substantial differences in the virus-receptor interaction, which can expand or reduce, or change tissue and species tropisms. Furthermore, the recent observation on the extracellular resistance of IDV to low pH inactivation versus the intracellular requirement of low pH for viral entry suggests a novel entry/fusion mechanism by which IDV employs to deliver its genome into the target cell. Three aims are proposed to address these hypotheses in this R01 application, which involve a comparative study of IDV and ICV. Aim 1 will elucidate the entry mechanism of IDV, while Aim 2 will define the molecular basis of the HEF receptor binding affinity and specificity and its impact on IDV tropism. Aim 3 is deigned to address how two IDV lineages, swine and bovine, read the glycan receptors differentially and how this information is transduced to different tissue and species tropisms between these two groups of IDVs. In summary, this proposal leverages the team's expertise in IDV research and novel aspects of IDV-receptor interaction and entry to elucidate the cross-species transmission mechanism of IDVs. Understanding molecular details of virus-receptor interaction may lead to development of novel strategies for the control and prevention of IDV and ICV infections in humans.