Elucidating the molecular determinants of Henipavirus envelope-antibody and envelope-receptor interactions on viral entry

阐明病毒进入时亨尼帕病毒包膜抗体和包膜受体相互作用的分子决定因素

• 批准号: 10296653
• 负责人: KASOPEFOLUWA Y. OGUNTUYO
• 金额: $ 4.44万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10296653
• 关键词: Address; Africa; Antibodies; Australia; Automobile Driving; Bangladesh; Binding; Binding Proteins; Brain Stem; Cameroon; Cell fusion; Cells; Cellular Membrane; Central Nervous System Infections; Cessation of life; Chimeric Proteins; China; Clinical; Collaborations; Complex; Costa Rica; Development; Directed Molecular Evolution; Disease; Disease Outbreaks; Encephalitis; Epidemic; Escape Mutant; Evolution; FDA approved; Family; Fever; Functional disorder; Genome; Ghana; Giant Cells; Glycoproteins; Goals; Hendra Virus; Henipavirus; Henipavirus Infections; Human; Immune; Immunization; Immunologics; Impairment; India; Individual; Infection; Mediating; Membrane Glycoproteins; Membrane Proteins; Molecular; Molecular Conformation; Monoclonal Antibodies; Mus; Mutagenesis; Mutation; Neurologic; Neurons; Nipah Virus; Paramyxovirus; Pathogenicity; Patients; Phenotype; Play; Population; Receptor Cell; Receptor Protein-Tyrosine Kinases; Recurrence; Research; Research Training; Resources; Respiratory distress; Risk; Role; Serology; Southeastern Asia; Structure; Testing; Thailand; Therapeutic; Tissues; Viral; Virus; Virus Diseases; Work; World Health Organization; Zoonoses; blind; cell type; experimental study; follow-up; high risk population; improved; member; mutant; neutralizing antibody; novel; novel therapeutics; pandemic disease; pathogen; receptor; receptor binding; respiratory; spillover event; tissue tropism; tool; trend

PROJECT SUMMARY: The identification of new Henipaviruses (HNVs) in Africa, China and Australia lend way to concerns about the risk of possible spillover events. Yet, there are no FDA approved therapeutics and the role of receptor usage on pathogenicity is still undetermined. Within this proposal, we aim to leverage our extensive preliminary results to further our understanding of the molecular determinants of envelope-antibody and envelope-receptor interactions on viral neutralization and viral pathogenicity. In recent work, we have identified an immune- accessible region on the NiV and HeV fusion glycoprotein that is targeted by several antibodies. Experiments proposed in Aim 1 will elucidate a mechanism for how these antibodies neutralize HNVs and will characterize novel antibodies against the divergent GhV fusion glycoprotein by utilizing a rapid, directed-evolution platform to identify escape mutants. Additionally, we have performed structure-guided mutagenesis to better understand HNV receptor binding protein and receptor interactions. The experiments directly proposed in Aim 2 will further characterize these mutants and assess the ability to confer use of this receptor to other HNVs using viruses. The work proposed here will ultimately support the development of HNV therapeutics and the understanding of the contributions of receptor usage on HNV pathogenicity.

项目总结： 在非洲、中国和澳大利亚发现新的亨尼帕病毒(HNV)引发了对 可能发生溢出事件的风险。然而，目前还没有FDA批准的治疗药物和受体使用在 致病性仍未确定。在这项提议中，我们的目标是利用我们广泛的初步成果 为了加深我们对包膜抗体和包膜受体分子决定因素的理解 病毒中和作用与病毒致病性的相互作用。在最近的工作中，我们已经确定了一种免疫- 新城疫病毒和戊型肝炎病毒融合糖蛋白上的可访问区域，是几种抗体的靶标。实验 目标1中提出的将阐明这些抗体如何中和HNV的机制，并将表征 利用快速定向进化平台获得针对发散型GHV融合糖蛋白的新抗体 以识别逃逸的突变体。此外，我们还进行了结构导向突变，以更好地 了解HNV受体结合蛋白和受体的相互作用。在AIM中直接提出的实验 2将进一步表征这些突变体，并评估将这种受体授予其他HNV使用的能力。 病毒。这里提出的工作最终将支持HNV疗法的发展和 了解受体的使用对HNV致病性的贡献。