Defining the determinants on the alphavirus receptor NRAMP required for virus bin

描述(由申请人提供)：甲型病毒与细胞受体的相互作用可能在决定病毒趋向性和驱动病毒诱导的疾病方面发挥重要作用。然而，介导甲型病毒进入的病毒受体却知之甚少。利用Sindbis病毒进行的全基因组筛查发现，NRAMP是昆虫细胞中潜在的甲病毒进入受体。更多的研究表明，NRAMP也是委内瑞拉马脑炎病毒的进入受体。此外，在哺乳动物细胞中，普遍表达的同系物NRAMP2可以介导这些甲型病毒的感染。我们的长期目标是剖析NRAMPs在甲型病毒的传染性和致病机制中的作用，目的是开发对抗这些病原体的策略。我们将通过剖析NRAMP上介导结合和进入的决定因素来研究这种重要的相互作用。此外，我们将对来自不同地方性和流行性宿主的NRAMP进行测序，以确定多态是否影响病毒感染。我们将利用我们开发的强大的分析方法来研究甲病毒在昆虫和哺乳动物细胞中的进入和感染，以探索NRAMPs在病毒感染中的作用。我们的中心假设是，解剖这些医学上重要的虫媒病毒与其受体的相互作用将揭示有助于开发针对这些尚未被研究的病原体的抗病毒治疗的机制，这些病原体目前还没有疫苗或疗法。

DESCRIPTION (provided by applicant): Alphavirus interactions with cellular receptors are likely to play a major role determining viral tropism and driving virus-induced disease. However, the viral receptors that mediate alphavirus entry are poorly understood. A genome wide screen using Sindbis virus identified NRAMP as a potential alphavirus entry receptor in insect cells. Additional studies suggest that NRAMP is also an entry receptor for Venezuelan Equine Encephalitis virus. Furthermore, in mammalian cells the ubiquitously expressed homolog, NRAMP2, can mediate infection of these alphaviruses. Our long-term goal is to dissect the role of NRAMPs in infectivity and pathogenesis of alphaviruses with the goal of developing strategies to combat these pathogens. We will study this important interaction by dissecting the determinants on NRAMPs that mediate binding and entry. Furthermore, we will sequence NRAMP from different enzootic and epizootic hosts to determine whether polymorphisms impact virus infection. We will take advantage of powerful assays that we have developed to study alphavirus entry and infection both in insect and mammalian cells to explore the role of NRAMPs in viral infection. Our central hypothesis is that dissecting the interactions of these medically important arboviruses with their receptor will reveal mechanisms that will aid in the development of antiviral treatments against these understudied pathogens for which there are no vaccines or therapeutics.