Host Defense Evasion by Fatal Emerging Paramyxoviruses

副粘病毒科有包膜负链RNA病毒快速感染人的能力 在广泛的宿主物种中传播往往是致命疾病的原因。这些病毒对人类和动物造成的威胁，最近在东南亚和澳大利亚爆发的致命性脑炎，由以前未被认识的副粘病毒，尼帕病毒和亨德拉病毒引起，这很好地说明了这一点。在副粘病毒科中，许多标准将尼帕病毒和亨德拉病毒区分为一个新属，亨尼帕病毒的代表。将它们与其他副粘病毒正相关的一个基因组特征是保守的富含半胱氨酸的蛋白质结构域，其是副粘病毒“V”蛋白的标志。其他副粘病毒的V蛋白通过诱导病毒的蛋白酶体降解而与宿主干扰素（IFN）信号转导的逃避和随后的先天性抗病毒应答有关。 IFN-应答转录因子，STAT 1或STAT 2。 初步研究表明，尼帕病毒V蛋白通过不同的机制逃避宿主IFN激活的防御。尼帕病毒V蛋白不诱导STAT蛋白降解，而是诱导含有STAT 1和STAT 2的高分子量细胞质复合物的形成。因此，尼帕病毒V蛋白表达改变稳态下的STAT亚细胞分布，阻止IFN刺激的STAT酪氨酸磷酸化，并阻断IFN诱导的STAT核重定位，导致对IFN α/β或IFN γ的细胞应答的抑制。 V蛋白位于副粘病毒-宿主界面，不仅是潜在的致病决定因子，而且也是药物干预和疫苗开发的治疗靶点，有助于控制自然爆发或生物恐怖主义威胁。将研究亨德拉病毒V蛋白抗细胞功能的分子基础，目的有三：（i）确定亨德拉病毒V蛋白阻止WN信号转导中STAT功能的能力（ii）定义参与亨德拉病毒IFN逃逸和亚细胞分布的关键功能结构域，以及（iii）表征V蛋白诱导的IFN逃逸复合物的组分和组装。

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.