Host Defense Evasion by Fatal Emerging Paramyxoviruses

副粘病毒科囊膜负链RNA病毒快速致病能力的研究 在广泛的宿主物种中传播往往是致命疾病的原因之一。这些病毒对人类和动物构成的威胁从最近东南亚和澳大利亚爆发的致命性脑炎中得到了很好的说明，这些脑炎是由以前未被发现的副粘病毒、尼帕病毒和亨德拉病毒引起的。在副粘病毒科中，许多标准将Nipah和Hendra病毒区分为一个新属--HenipaVirus。将它们与其他副粘病毒积极联系的一个基因组特征是一个保守的富含半胱氨酸的蛋白结构域，这是副粘病毒V蛋白的标志。其他副粘病毒的V蛋白通过诱导蛋白酶体降解，与逃避宿主干扰素信号转导和随后的先天抗病毒反应有关。 干扰素反应转录因子，STAT1或STAT2。 初步研究表明，Nipah病毒V蛋白通过一种不同的机制逃避宿主干扰素激活的防御。Nipah病毒V蛋白不能诱导STAT蛋白降解，而是诱导含有STAT1和STAT2的高分子量细胞质复合体的形成。因此，Nipah病毒V蛋白的表达改变了稳定状态下STAT的亚细胞分布，阻止了IFN刺激的STAT酪氨酸磷酸化，并阻止了干扰素诱导的STAT核重新定位，导致抑制细胞对IFNpha/β或IFNGamma的反应。 V蛋白位于副粘病毒-宿主界面，不仅是一个潜在的致病决定因素，而且是药物干预和疫苗开发的治疗靶点，有助于控制自然暴发或生物恐怖威胁。研究汉尼帕病毒V蛋白抗细胞功能的分子基础有三个目的：(1)确定Hendra病毒V蛋白在WN信号转导中阻止STAT功能的能力；(2)确定与汉尼帕病毒干扰素逃逸和亚细胞分布有关的关键功能结构域；(3)鉴定V蛋白诱导的干扰素逃避复合体的组成和组装。

The ability of enveloped negative strand RNA viruses of the family Paramyxoviridae to rapidly disseminate throughout a broad range of host species is often a cause of fatal diseases. The threat to humans and animals posed by these viruses is well illustrated by recent outbreaks of fatal encephalitis in southeast Asia and Australia resulting from the previously unrecognized Paramyxoviruses, Nipah virus and Hendra virus. Within the Paramyxoviridae, many criteria have distinguished Nipah and Hendra viruses as representative of a new genus, Henipavirus. One genomic feature that positively links them to other paramyxoviruses is a conserved cysteine-rich protein domain that is the hallmark of paramyxovirus 'V' proteins. The V proteins of other paramyxoviruses have been linked to evasion of host interferon (IFN) signal transduction and subsequent innate antiviral responses, by inducing proteasomal degradation of the IFN-responsive transcription factors, STAT1 or STAT2. Preliminary investigations demonstrate that the Nipah virus V protein evades host IFN-activated defenses by a different mechanism. Nipah virus V protein does not induce STAT protein degradation, but instead induces formation of high molectflar weight cytoplasmic complexes that contain STAT1 and STAT2. Thus, Nipah virus V protein expression alters STAT subcellular distribution in the steady-state, prevents IFNstimulated STAT tyrosine phosphorylation, and blocks IFN-induced STAT nuclear relocalization, resulting in inhibition of cellular responses to either IFNalpha/beta or IFNgamma. The V protein is situated at the paramyxovirus-host interface and is not only a potential pathogenesis-determining factor, but also represents a therapeutic target for pharmaceutical intervention and vaccine development, contributing to an armamentarium for the control of natural outbreaks or bioterrorist threats. The molecular basis for Henipavirus V protein anti-cellular functions will be investigated with three aims to: (i) Determine the ability of Hendra virus V protein to prevent STAT function in WN signal transduction (ii) Define critical functional domains involved in Henipavirus IFN evasion and subcellular distribution, and (iii) Characterize components and assemble of V protein-induced IFN evasion complexes.