Host range and pathogenesis of paramyxoviruses

描述(申请人提供)：副粘病毒包括多种人类病原体，例如会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。人们对定义密切相关病毒宿主范围的因素知之甚少。我们的目标是利用人副流感病毒1型(HPIV1)和小鼠副流感病毒1型(仙台病毒)来确定限制副粘病毒宿主范围的机制(S)。HPIV1和仙台病毒在结构和氨基酸序列上高度同源，但有不同的宿主种类，人和鼠。 我们的初步结果表明，hPIV1需要人类来源的未知宿主细胞因子(S)来转录病毒基因组。病毒基因组在小鼠细胞中的转录效率低下，这表明对物种特异性宿主细胞因子的需求在限制hPIV1的宿主范围方面发挥了关键作用。我们还发现，这些病毒的抗干扰素反应具有物种特异性，hPIV1在人细胞中对抗干扰素活性，但在小鼠细胞中不起作用，而仙台病毒则拮抗小鼠干扰素活性，但在人细胞中不起作用。这些结果使我们推测，病毒抗干扰素活性的物种特异性限制了1型副流感病毒的宿主范围。 在本项目中，我们将在目标1中鉴定转录所需的宿主细胞因子(S)，并评价其在hPIV1宿主特异性中的作用。此外，我们将在目标2中分析hPIV1拮抗干扰素反应的分子机制。目标3中将表征病毒抗干扰素活性的物种特异性和干扰素诱导抗病毒活性的机制。我们相信，了解使病毒对人类具有感染性和致病性的分子机制将对改善公共卫生具有重要意义。我们的研究还将为我们开发抗病毒试剂提供线索，这种试剂可以阻断对人类病毒生长至关重要的特定病毒-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.