Influenza D Virus Entry and Tissue Tropism

D 型流感病毒进入和组织趋向性

• 批准号: 10240750
• 负责人: FENG LI
• 金额: $ 51.83万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240750
• 关键词: Acids; Address; Affinity; Agreement; Animals; Antiviral Agents; Asia; Binding; Biological; Carbon; Cattle; Cavia; Cells; Chimeric Proteins; Comparative Study; Data; Dependence; Development; Disease; Disease Outbreaks; Distant; Endocytosis; Equus caballus; Europe; Family suidae; Ferrets; Genetic; Genome; Health; Human; Immunity; Infection; Influenza; Influenza A virus; Influenza C Virus; Influenza D Virus; Influenza prevention; Investigation; Lead; Light; Membrane Fusion; Molecular; Mutation; N-Acetylneuraminic Acid; N-glycolylneuraminic acid; Oklahoma; Pathway interactions; Periodicals; Polysaccharides; Positioning Attribute; Public Health; Research; Research Priority; Resistance; Ruminants; Serology; Sialic Acids; Specificity; Structure; Tissues; Tropism; Vaccines; Viral; Viral Genome; Virus; Virus Diseases; Virus Receptors; Work; Zoonoses; base; chemical group; cross-species transmission; extracellular; hemagglutinin esterase; influenzavirus; insight; novel; novel strategies; preference; receptor; receptor binding; sialic acid receptor; tissue tropism; trait; virus tropism; Acids; Address; Affinity; Agreement; Animals; Antiviral Agents; Asia; Binding; Biological; Carbon; Cattle; Cavia; Cells; Chimeric Proteins; Comparative Study; Data; Dependence; Development; Disease; Disease Outbreaks; Distant; Endocytosis; Equus caballus; Europe; Family suidae; Ferrets; Genetic; Genome; Health; Human; Immunity; Infection; Influenza; Influenza A virus; Influenza C Virus; Influenza D Virus; Influenza prevention; Investigation; Lead; Light; Membrane Fusion; Molecular; Mutation; N-Acetylneuraminic Acid; N-glycolylneuraminic acid; Oklahoma; Pathway interactions; Periodicals; Polysaccharides; Positioning Attribute; Public Health; Research; Research Priority; Resistance; Ruminants; Serology; Sialic Acids; Specificity; Structure; Tissues; Tropism; Vaccines; Viral; Viral Genome; Virus; Virus Diseases; Virus Receptors; Work; Zoonoses; base; chemical group; cross-species transmission; extracellular; hemagglutinin esterase; influenzavirus; insight; novel; novel strategies; preference; receptor; receptor binding; sialic acid receptor; tissue tropism; trait; virus tropism

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.

项目摘要 新型流感病毒（IDV）利用牛作为主要储层，周期性溢出到 其他哺乳动物宿主在内，包括猪和马。具有更大的公共健康重要性，血清学 已经证明了人类IDV感染的证据。初步调查显示 IDV与人类9-O-乙酰化的N-乙酰神经氨酸酸（NEU5,9AC2）结合，人类的受体 流感病毒（ICV）和非人类N-糖苷神经氨酸（NEU5GC9AC），并且可能使用 他们进入病毒。进一步的功能研究表明，IDV在识别同时更有效 人neu5,9AC2-和非人类neu5gc9ac的聚糖比ICV，而ICV似乎 优先与非人类NEU5GC9AC上的人Neu5,9AC2结合。同意这一点，ICV有 人类作为水库的有限宿主范围。这些结果表明IDV和ICV在 与唾液酸（SA）进行感染。假设是在 居住在血凝素 - 酯酶融合中的受体结合口袋的序列和结构 （HEF）IDV和ICV之间的蛋白质会在病毒受体相互作用中发生实质性差异， 可以扩展或减少或改变组织和物种的向流。此外，最近 观察IDV对低pH失活的细胞外电阻与细胞内的抗性 低pH的要求对病毒进入的要求提出了一种新颖的进入/融合机制 将其基因组传递到靶细胞中。提出了三个目标来解决这些假设 R01应用，涉及IDV和ICV的比较研究。 AIM 1将阐明条目 IDV的机制，而AIM 2将定义HEF受体结合亲和力的分子基础和 特异性及其对IDV潮流的影响。 AIM 3被否定，以解决两个IDV谱系，猪和 牛，差异阅读聚糖受体，以及如何将这些信息传递到不同 这两组IDV之间的组织和物种向朝向主义。总而言之，该提议利用了 团队在IDV研究和IDV受体互动的新颖方面的专业知识和阐明 IDV的跨物种传输机制。了解病毒受体的分子细节 互动可能会导致发展和预防IDV和ICV的新型策略 人类感染。