Host range and pathogenesis of paramyxoviruses

性状（由申请方提供）：副粘病毒包括多种人类病原体，如在幼儿中引起严重呼吸道感染的人类副流感病毒。这一组还包括动物病原体，它们在结构和序列上与相应的人类病毒相似，但具有不同的宿主范围。对于决定密切相关病毒宿主范围的因素知之甚少。我们的目标是使用人副流感病毒1型（hPIV 1）和鼠副流感病毒1型（仙台病毒）确定限制副粘病毒宿主范围的机制。hPIV 1和仙台病毒在结构和氨基酸序列上高度同源，但具有不同的宿主种属（人与小鼠）。 我们的初步结果表明，hPIV 1需要未知的人类来源的宿主细胞因子来转录病毒基因组。病毒基因组的转录在小鼠细胞中是低效的，这表明物种特异性宿主细胞因子的需求在hPIV 1的宿主范围限制中起关键作用。我们还发现这些病毒的抗IFN反应是种特异性的，hPIV 1在人细胞中对抗IFN活性，但在鼠细胞中不对抗IFN活性，而仙台病毒拮抗鼠IFN活性，但在人细胞中不对抗IFN活性。这些结果使我们推测，病毒抗IFN活性的种属特异性限制了1型副流感病毒的宿主范围。 在本项目中，我们将鉴定转录所需的宿主细胞因子，并评估其在hPIV 1的宿主特异性中的作用。进一步分析hPIV 1拮抗IFN应答的分子机制。病毒抗IFN活性的种属特异性和IFN诱导的抗病毒活性的机制将在目的3中表征。我们相信，了解使病毒对人类具有传染性和致病性的分子机制将大大有助于改善公共卫生。我们的研究还将为我们开发抗病毒试剂提供线索，这些试剂可以阻断病毒在人类中生长所必需的特定病毒-宿主相互作用。

DESCRIPTION (provided by applicant): Paramyxoviruses include a variety of human pathogens, such as human parainfluenza viruses that cause serious respiratory infections among young children. This group also includes animal pathogens which are similar to the corresponding human virus in structure and sequences, but have distinct host ranges. Little is known about the factors that define the host range of closely related viruses. Our goal is to identify the mechanism(s) that restrict the host range of paramyxovirus using human parainfluenza virus type 1 (hPIV1) and murine parainfluenza virus type 1 (Sendai virus). The hPIV1 and Sendai virus are highly homologous in structure and amino acid sequences but have distinct host species, human vs. mouse. Our preliminary results suggest that hPIV1 requires unidentified host cell factor(s) of human origin for transcription of viral genome. Transcription of viral genome was inefficient in murine cells, suggesting that requirement of a species-specific host cell factor plays a key role in host range restriction of hPIV1. We also found that anti-IFN response of these viruses is species specific, hPIV1 counteracts IFN activity in human cells but not in murine cells, while Sendai virus antagonizes murine IFN activity but not in human cells. These results led us to hypothesize that species specificity of viral anti-IFN activity restrict the host range of type 1parainfluenza viruses. In this project, we will identify the host cell factor(s) required for transcription and evaluate its role in host specificity of hPIV1 in aim 1. Furthermore, we will analyze the molecular mechanism of hPIV1 to antagonize IFN response in aim 2. The species specificity of viral anti-IFN activity and mechanisms of IFN-induced antiviral activities will be characterized in aim 3. We believe that understanding the molecular mechanisms that make virus infectious and pathogenic to humans will significantly contribute to the public health improvement. Our research will also give us clues to develop antiviral reagents that block specific virus-host interactions essential for viral growth in humans.