Dissecting the receptor-mediated infection mechanisms of hantaviruses

汉坦病毒在人类中引起两种疾病综合征。新世界病原体，包括Sin Nombre病毒（SNV）和安第斯病毒（ANDV），在美洲引起高度致命的汉坦病毒心肺综合征（HCPS），而旧世界病原体，包括汉坦病毒（HTNV）和普马拉病毒（PUUV），在欧亚大陆引起较不致命的肾综合征出血热（HFRS）。所有已知的疫情都可以追溯到汉坦病毒从其啮齿动物宿主宿主传播的人畜共患传播，人口增长和气候变化的加速可能会在未来几十年增加汉坦病毒爆发的频率和规模。目前，还没有获得批准的抗汉坦病毒疫苗和治疗方法，它们的开发受到我们对病毒-宿主分子相互作用的理解的重大空白的挑战，这种相互作用是感染、疾病和传播的基础。目前的证据表明，人类汉坦病毒病是由毛细血管内皮细胞中的非溶细胞病毒感染和复制以及随之而来的失调引起的。然而，内皮细胞感染的分子基础，包括汉坦病毒进入的必要受体的身份，仍然知之甚少。我们最近发现了原钙粘蛋白-1 (PCDH1)，它是钙粘蛋白超家族的一员，在肺内皮细胞和上皮细胞中表达，是内皮细胞中汉坦病毒的一种新的关键候选受体。我们的总体目标是确定PCDH1介导汉坦病毒进入和感染内皮细胞的分子机制；研究这种病毒-受体相互作用对汉坦病毒体内毒力和发病机制的影响；确定其作为开发抗病毒治疗药物的靶标的效用；并探索其作为影响汉坦病毒宿主范围的宿主屏障的潜在作用。

Hantaviruses cause two disease syndromes in humans. New World agents, including Sin Nombre virus (SNV) and Andes virus (ANDV), cause a highly fatal hantavirus cardiopulmonary syndrome (HCPS) in the Americas, whereas Old World agents, including Hantaan virus (HTNV) and Puumala virus (PUUV), cause a less fatal hemorrhagic fever with renal syndrome (HFRS) in Eurasia. All known outbreaks have been traced to the zoonotic transmission of hantaviruses from their rodent host reservoirs, and human population growth and accelerating climate change may increase the frequency and size of hantavirus outbreaks in the coming decades. At present, no approved anti-hantavirus vaccines and therapeutics are available—their development is challenged by crucial gaps in our understanding of the virus-host molecular interactions that underpin infection, disease, and transmission. Current evidence indicates that human hantavirus disease arises from non-cytolytic viral infection and replication in capillary endothelial cells, and their attendant dysregulation. However, the molecular basis of endothelial cell infection, including the identities of essential receptor(s) for hantavirus entry, remains poorly understood. This proposal is centered on our recent discovery of protocadherin-1 (PCDH1), a member of the cadherin superfamily expressed in lung endothelial and epithelial cells, as a novel and critical candidate receptor for hantaviruses in endothelial cells. Our overall goals are to define the molecular mechanism by which PCDH1 mediates hantavirus entry and infection of endothelial cells; investigate the implications of this proposed virus–receptor interaction for hantavirus virulence and pathogenesis in vivo; determine its utility as a target for the development of antiviral therapeutics; and explore its potential role as a host barrier that influences hantavirus host range.