Tropism, pathogenicity, and potential for zoonotic spillover of emergent henipa- and henipa-like viruses

新出现的亨尼帕病毒和亨尼帕样病毒的趋向性、致病性和人畜共患病溢出的可能性

• 批准号: 9749970
• 负责人: Benhur Lee
• 金额: $ 58.48万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-26 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9749970
• 关键词: Africa; Animals; Antibodies; Australia; Automobile Driving; Binding Sites; Brain Stem; Calculi; Cameroon; China; Chiroptera; Complex; Disease; Ebola virus; Encephalitis; Epidemic; Event; Exhibits; Fruit; Ghana; Glycoproteins; Goals; Hendra Virus; Henipavirus; Human; Infection; Ligands; Livestock; Monoclonal Antibodies; Neuronal Dysfunction; Paramyxovirinae; Paramyxovirus; Pathogenicity; Phylogenetic Analysis; Population; Proteins; Risk; Role; Southeastern Asia; Structure; Tropism; Vaccine Design; Viral; Virulence; Virus; Zoonoses; blind; high risk; mortality; neutralizing antibody; novel; pathogen; pathogenic virus; polyclonal antibody; receptor; receptor binding; respiratory; scaffold; transmission process

ABSTRACT Nipah (NiV) and Hendra (HeV) viruses are highly pathogenic type species of the Henipavirus (HNV) genus within the Paramyxovirinae. Zoonotic transmission of NiV and HeV from their natural fruit bat reservoirs to humans can result in mortality rates in excess of 90%. Originally thought to be limited to Southeast Asia and Australia, the recent discovery of numerous divergent clades of HNVs across Africa, and of Henipa-like viruses (HNLV) in China such as the Mojiang paramyxovirus (MojPV), qualitatively changes the risk- calculus associated with the possible global emergence of these zoonotic viruses. Indeed, we recently found evidence for HNV spillover into human populations at high-risk for zoonotic transmission in Cameroon, which raise urgent questions about potential spillover events that may have remained undetected or misdiagnosed. The recent Ebola epidemic in West Africa underscores the importance of understanding the mechanisms of zoonotic spillover and transmission of highly pathogenic emerging viruses. HNVs use EphrinB2 and EphrinB3, highly conserved cellular proteins, as viral entry receptors. The recent discovery of novel HNVs with differential usage of EphrinB2 and B3 provides new opportunities to study how receptor usage contributes to the pathogenicity and potential for zoonotic spillover of these emergent HNVs. Our overall goal is to elucidate the envelope-receptor interactions of HNVs and HNLVs that contribute to viral tropism, pathogenicity, transmissibility, and the potential for zoonotic spillover. Our primary objective is to understand the structure-function correlates of envelope- receptor interactions in the pathobiology of HNV/HNLV zoonotic infections. A secondary objective is to leverage that understanding to interrogate the rational basis for a vaccine design that might elicit antibodies that are more broadly neutralizing and effective against an ever-expanding spectrum of diverse HNVs. Our driving hypothesis is: the structural plasticity of HNV-Gs accounts for the differential efficiency and choice of receptor usage exhibited by divergent HNVs, and that this contributes to a virulence spectrum among these zoonotic viruses that is equally diverse. To achieve our objectives and interrogate our driving hypothesis, we propose the following Specific Aims: (1) Investigate the role of receptor usage and choice in virus pathogenicity. (2) Evaluate how attachment protein-receptor interactions contribute to transmissibility and the potential for zoonotic spillover. (3) Examine the implications of the structural and phylogenetic diversity of HNVs on vaccine design.

抽象的 尼帕病毒 (NiV) 和亨德拉病毒 (HeV) 是亨尼帕病毒 (HNV) 属的高致病性病毒 属于副粘病毒亚科。 NiV 和 HeV 从其天然果蝠宿主传播到 人类造成的死亡率超过90%。原本以为仅限于东南亚 和澳大利亚，最近在非洲发现了许多不同的 HNV 分支，以及类似 Henipa 的分支 中国的病毒（HNLV），例如墨江副粘病毒（MojPV），从本质上改变了风险- 与这些人畜共患病毒可能在全球出现有关的微积分。确实，我们最近 发现 HNV 溢出到人畜共患传播高风险人群的证据 喀麦隆，这对可能仍然存在的潜在溢出事件提出了紧急问题 未被发现或误诊。最近西非的埃博拉疫情凸显了 了解人畜共患高致病性新兴病毒溢出和传播的机制 病毒。 HNV 使用高度保守的细胞蛋白 EphrinB2 和 EphrinB3 作为病毒进入受体。这 最近发现的具有不同用途的 EphrinB2 和 B3 的新型 HNV 为 研究受体的使用如何导致这些疾病的致病性和人畜共患病溢出的可能性 新兴 HNV。我们的总体目标是阐明 HNV 的包膜受体相互作用 HNLV 有助于病毒的趋向性、致病性、传播性和潜在的 人畜共患病的溢出效应。我们的主要目标是了解信封的结构-功能相关性 HNV/HNLV 人畜共患感染病理学中的受体相互作用。次要目标是 利用这种理解来质疑可能引发抗体的疫苗设计的合理基础 这些措施能够更广泛地中和和有效地对抗不断扩大的不同 HNV 范围。我们的 驱动假设是：HNV-G 的结构可塑性解释了不同的效率和选择 不同 HNV 表现出的受体使用情况，这有助于形成毒力谱 这些人畜共患病病毒同样多种多样。实现我们的目标并质疑我们的驾驶能力 假设，我们提出以下具体目标： (1) 研究受体的使用和选择在病毒致病性中的作用。 (2) 评估附着蛋白-受体相互作用如何促进传播性和 人畜共患病溢出的可能性。 (3) 检验HNV的结构和系统发育多样性对疫苗的影响 设计。