Transmissibility of avian influenza viruses in mammals

禽流感病毒在哺乳动物中的传播能力

• 批准号: 8503049
• 负责人: YOSHIHIRO KAWAOKA
• 金额: $ 60.37万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503049
• 关键词: Address; Affect; Amino Acids; Animals; Antibodies; Area; Avian Influenza A Virus; Basic Science; Binding; Biological; Biological Assay; Birds; Case Fatality Rates; Disease; Egypt; Ferrets; Foundations; Funding; Genes; Genetic; Genetic Transcription; H5 hemagglutinin; Head; Hemagglutinin; Human; Incidence; Indonesia; Infection; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Interferons; Intracellular Transport; Libraries; Mammals; Modeling; Molecular; Monitor; Mus; Mutation; Other Genetics; Pathogenicity; Population; Property; Proteins; Public Health; Reassortant Viruses; Reporting; Research; Research Design; Research Project Grants; Role; Specificity; System; Testing; Time; Vietnam; Viral Genes; Virus; base; influenzavirus; mutant; novel; pandemic disease; public health relevance; receptor; receptor binding; respiratory; tool; transmission process

DESCRIPTION (provided by applicant): Since 1997, highly pathogenic avian influenza viruses of the H5N1 subtype have infected humans with high case fatality rates, although no sustained human-to-human transmission has yet been reported. Currently, the molecular features and mechanisms that would result in human-to-human transmission of H5N1 viruses are not fully understood. Indeed, several attempts in the past to select transmissible H5 viruses (which typically do not transmit among mammals) were not successful, suggesting that influenza virus transmissibility is determined by several currently unknown factors. Recently, we screened H5 virus libraries possessing random mutations in the globular head region of the hemagglutinin (HA) protein and identified mutant H5 HAs that acquired the ability to bind to human-type receptors. These mutant H5 HAs did not support virus transmission among ferrets (an established influenza virus transmission model) via respiratory droplets, but acquired this ability after two passages of the virus in these animals, which resulted in the selection of additional mutations in HA. This marks the first conversion of an H5 virus that does not transmit among ferrets into one with efficient respiratory droplet transmission. Based on this finding, we propose to decipher the determinants of H5N1 virus transmission in mammals. In Aim 1, we plan "To Identify the Mechanisms That Control H5N1 Virus Transmissibility in Mammals". To gain a better understanding of the mutations in HA that result in transmissible viruses, we will select transmissible viruses based on H5 HA proteins derived from different subclades that have caused human infections. Our recent study suggested that HA stability may contribute to virus transmissibility. To test this concept, we also plan to identify mutations in HA that increase HA stability and then test these mutations for their significance in virus transmissibility. The HA proteins of all ferret-transmissible H5N1 viruses will then be characterized for their receptor-binding specificity, their structural consequences, their effects in other genetic backgrounds, and their pathogenicity in mice and ferrets. Mutations in HA that allow avian influenza viruses to bind to human-type receptors are most likely a prerequisite for transmission among mammals; however, findings by us and others indicate that human-type receptor binding is not sufficient for respiratory droplet transmission among ferrets, and that other viral genes also contribute to transmissibility. In Aim 2 ("To Characterize the Contribution of Viral Genes Other than HA to H5N1 Virus Transmissibility", we plan to passage non-transmissible viruses of different genetic backgrounds in ferrets to select transmissible mutants. Selected mutations will be characterized for their biological effects, using established assays for internalization, intracellular transport replication and transcription, assembly and budding, and interferon antagonism. Collectively, these studies are expected to generate critical information about the molecular determinants and mechanisms of H5N1 virus transmissibility in mammals.

描述（由申请人提供）：自1997年以来，H5N1亚型的高度致病性禽流感病毒感染了病例高病情的人类，尽管尚未报道过持续的人类到人类传播。当前，尚未完全了解将导致人类到人类传播的分子特征和机制。实际上，过去有几次尝试选择可传播的H5病毒（通常在哺乳动物之间传播）并不成功，这表明流感病毒的传播性是由几种当前未知的因素确定的。最近，我们筛选了在血凝素（HA）蛋白的球形头部区域中具有随机突变的H5病毒文库，并鉴定出突变型H5具有与人型受体结合的能力。这些突变体H5不支持通过呼吸液滴（已建立的流感病毒传播模型）之间的病毒传播，但获得了这种能力 在这些动物中的病毒两次通过后，导致选择了HA中的其他突变。这标志着H5病毒的第一次转化，该病毒不会在雪貂之间传播到具有有效的呼吸液滴传递的一种中。基于这一发现，我们提出了 破译哺乳动物中H5N1病毒传播的决定因素。在AIM 1中，我们计划“确定控制哺乳动物中H5N1病毒传播的机制”。为了更好地了解导致可传播病毒的HA突变，我们将基于从引起人类感染的不同子基质中得出的H5 HA蛋白选择可传染性病毒。我们最近的研究表明，HA稳定性可能有助于病毒的传播。为了测试这个概念，我们还计划鉴定HA中增加HA稳定性的突变，然后测试这些突变在病毒传播中的重要性。然后，所有雪貂经过智能H5N1病毒的HA蛋白将以其受体结合特异性，结构后果，其他遗传背景的影响以及 它们在小鼠和雪貂中的致病性。 HA中允许禽流感病毒结合的突变 对人型受体很可能是哺乳动物传播的先决条件。但是，我们和其他人的发现表明，人类型受体结合不足以使雪貂之间的呼吸液滴传递，并且其他病毒基因也有助于传播。在目标2中（“为了表征HA对H5N1病毒传播的其他病毒基因的贡献”，我们计划通过雪貂的不同遗传背景的不同遗传背景的不可经常性病毒来选择可传播的突变体。将使用其生物学效应来表征其选择的突变，以实现其内部倾向，内部倾斜的三个研究和固定性的分类，并进行了固定的分类，并构成了固定的分类，并构成了固定的分类，并进行了构成，并构成了构建，并构成了启发。预计将产生有关哺乳动物中H5N1病毒传播性的分子决定因素和机制的关键信息。