Cellular pathways involved in new world arenavirus infections

新大陆B分支病毒(NWA)，特别是Junin(JUNV)和Machupo(MACV)是 与南美洲爆发的病毒性出血热有关。JUNV和MACV感染 代表来自啮齿动物的人畜共患病，两者都通过气雾剂传播；因此，NWA是潜在的 生物恐怖主义特工。JUNV尤其是最近的病原体名单中仅有的三种病毒之一 由国土安全部开发，在他们的评估中代表了最重要的 美国面临的生物恐怖主义威胁。近年来，转铁蛋白受体1(TfR1)被鉴定为一种细胞因子。 新大陆致病亚型病毒的受体。然而，人们对以下步骤知之甚少 病毒/TfR1细胞表面相互作用，有证据表明其他分子在NWA进入中发挥作用。 此外，尽管JUNV和MACV有效地利用其宿主啮齿动物物种的TfR1进入，但它们 似乎只对受感染的人有致病性。我们提出了几种方法来确定共同因素 支持将NWA感染作为更好地了解这些病毒在人类中的致病性的一种手段。 这些包括cdna表达、siRNA和化学文库筛选，以确定 可作为感染治疗干预的靶点。所有这些都依赖于基于蜂窝的高吞吐量 宾夕法尼亚大学的筛选(HTCS)核心，将支持RCE计划I和II中的项目。我们还建议 利用MMTV囊膜和JUNV野生型疫苗构建JUNV/MMTV嵌合杂合病毒 伪型JUNV和MMTV病毒核心的gP蛋白。这些伪型 将为我们提供一种研究ArenaVirus基因产物如何引起致病性的手段。嵌合者 病毒将用于HTCS屏幕上的NFicB和IRF3报告细胞，以开始揭开激活 导致细胞因子风暴的途径。因为目前还没有用于治疗或感染后的抗病毒药物 B分支病毒的预防性治疗，参与的辅助因素的识别 JUNV和MACV的进入并可能参与其发病机制，有可能导致其发生发展 治疗由这些病毒引起的出血热的新疗法。

The New World clade B arenaviruses (NWA), particularly Junin (JUNV) and Machupo (MACV) are associated with outbreaks of viral hemorrhagic fever in South America. JUNV and MACV infections represent zoonoses from rodents and are both transmitted through aerosols; thus, the NWAs are potential bioterrorism agents. JUNV in particular is one of only three viruses included in the recent list of agents developed by the Department of Homeland Security that represent in their assessment the most significant bioterrorism threats faced by the US. Recently, transferrin receptor 1 (TfR1) was identified as a cellular receptor for the pathogenic New World arenaviruses. However, little is known about the steps subsequent to virus/TfR1 cell surface interaction and there is evidence that other molecules play a role in NWA entry. Moreover, although JUNV and MACV efficiently use TfR1 from their host rodent species for entry, they appear to only be pathogenic in infected humans. We propose several approaches to identify co-factors that support NWA infection as a means for better understanding the pathogenicity of these viruses in humans. These include cDNA expression, siRNA and chemical library screening, to identify genes and pathways that could serve as targets for therapeutic intervention of infection. All rely on the high-throughput, cell-based screening (HTCS) core at Penn, that will support projects in RCE Programs I and II. We also propose creating chimeric JUNV/MMTV hybrid viruses using the MMTV envelope and JUNV wild type and vaccine strain (candid #1) GP proteins to pseudotype JUNV and MMTV virus cores, respectively. These pseudotypes will provide us with a means of studying how arenavirus gene products cause pathogenicity. The chimeric viruses will be used for HTCS screens of NFicB and IRF3 reporter cells, to begin to uncover the activation pathways that lead to the cytokine storm. As there are currently no anti-virals in use for therapeutic or postinfection prophylactic treatment of the clade B arenaviruses, the identification of co-factors that participate in JUNV and MACV entry and perhaps contribute to pathogenesis has the potential to lead to the development of novel therapies for hemorrhagic fevers cause by these viruses.