FLAVIVIRUS ENVELOPE PROTEIN AND COMPLEXES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 登革热病毒有四种血清型。在感染患者中引发的许多抗体仅中和一种血清型。然而，登革病毒型特异性抗体可通过介导病毒附着于骨髓细胞上的Fc受体，促进其他登革热血清型进入骨髓细胞。抗体依赖性感染增强（ADE）显著增加了疾病的严重程度。获得所有四种登革热血清型的详细分子图谱将使我们能够绘制负责ADE的血清型之间的差异。 黄病毒利用其包膜蛋白E结合受体并通过内吞作用进入细胞。内体的pH降低触发了E.在这种构象重排中释放的能量用于使病毒脂质膜朝向内体膜弯曲，导致两种膜融合。膜融合将病毒基因组递送到细胞质中，因此是病毒进入的关键步骤。 建立在我们的结构研究E从登革热和西尼罗河病毒在融合前和融合后的状态，我们的目标是完成我们的图片黄病毒膜融合通过确定全长E胞外域的结构。我们还旨在确定与具有治疗性抗病毒特性的各种肽复合的E的结构。我们的工作将为合理设计和筛选抑制病毒进入的药物提供一个框架。 目前还没有针对西尼罗河病毒或登革热病毒的治疗方法或疫苗，这两种病毒都是新出现的全球健康威胁。疫苗设计受到大多数中和表位的高变异性和ADE的阻碍，ADE被认为是登革热死亡的主要原因。为了指导疫苗设计，我们将研究结合黄病毒包膜蛋白保守表位的抗体中和的结构基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There are four serotypes of dengue virus. Many antibodies elicited in infected patients neutralize only one serotype. However, serotype-specific antibodies can facilitate the entry of other dengue serotypes into myeloid cells by mediating attachment of the virus to the Fc receptors on those cells. Antibody-dependent enhancement of infection (ADE) significantly worsens the severity of disease. Obtaining a detailed molecular landscape of all four dengue serotypes will allow us to map the differences between serotypes that are responsible for ADE. Flaviviruses use their envelope protein, E, to bind a receptor and enter cells by endocytosis. The reduced pH of an endosome triggers a conformational rearrangement in E. The energy released in this conformational rearrangement is used to bend the viral lipid membrane towards the endosomal membrane, resulting in fusion of the two membranes. Membrane fusion delivers the viral genome into the cytoplasm and is therefore a key step in viral entry. Building on our structural studies of E from dengue and West Nile viruses in the pre- and postfusion states, we aim to complete our picture of flaviviral membrane fusion by determining the structures of the full-length E ectodomain. We also aim to determine the structure of E in complex with various peptides with therapeutic antiviral properties. Our work will provide a framework for the rational design and screening of drugs that inhibit viral entry. There are currently no treatments or vaccines available for West Nile or dengue virus, which are both emerging global health threats. Vaccine design has been hampered by the high variability of most neutralizing epitopes and by ADE, which is thought to be a major cause of mortality from dengue fever. In an effort to guide vaccine design, we will study the structural basis for neutralization by antibodies that bind conserved epitopes in flaviviral envelope proteins.