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.

摘要 尼帕(Niv)和亨德拉(HEV)病毒是亨尼帕病毒(HNV)属的高致病性模式物种 在副粘病毒亚科内。新城疫和戊型肝炎病毒从其天然果蝠蓄水池传播到 人类可能导致超过90%的死亡率。最初被认为仅限于东南亚 和澳大利亚，最近在非洲发现了许多不同的HNV分支，以及Henipa类病毒 中国中的病毒，如墨江副粘病毒，从质上改变了风险- 与这些人畜共患病毒可能在全球出现有关的微积分。的确，我们最近 发现HNV蔓延到人畜共患传播高危人群的证据 喀麦隆，这对潜在的溢出事件提出了紧迫的问题，这些事件可能已经 未被发现或被误诊。最近西非的埃博拉疫情突显了 了解新出现的人畜共患病溢出和传播机制 病毒。HNV使用高度保守的细胞蛋白EPhinB2和EPhinB3作为病毒进入受体。这个 最近发现的具有不同用途的新型HNV为以下方面提供了新的机会 研究受体的使用如何促进这些病毒的致病性和潜在的人畜共患病溢出 新出现的HNV。我们的总体目标是阐明HNV和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包膜的结构-功能关联-- HNV/HNLV人畜共感染病理生物学中的受体相互作用次要目标是 利用这一理解来询问可能引发抗体的疫苗设计的合理基础 它们对不断扩大的各种HNV病毒具有更广泛的中和作用和有效性。我们的 驱动假说是：HNV-Gs的结构可塑性解释了差异效率和选择 不同的HNV表现出的受体使用情况，这有助于在 这些人畜共患病病毒是同样多样的。为了实现我们的目标并审问我们的驾驶 假设，我们提出了以下具体目标： (1)探讨受体的使用和选择在病毒致病中的作用。 (2)评估附着蛋白-受体相互作用如何促进传递性和 人畜共患病的潜在溢出效应。 (3)研究HNV的结构和系统发育多样性对疫苗的影响 设计。