Distinct and overlapping roles of Nipah virus P gene products in modulating the human endothelial cell antiviral response.
Distinct and overlapping roles of Nipah virus P gene products in modulating the human endothelial cell antiviral response.
复制标题
DOI：
10.1371/journal.pone.0047790
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Spiropoulou CF
中科院分区：
文献类型：
--
作者：
Lo MK;Peeples ME;Bellini WJ;Nichol ST;Rota PA;Spiropoulou CF
尼帕病毒（NiV）是一种高致病性人畜共患副粘病毒，可在高达75%的感染者中引起致命性脑炎。与其他副粘病毒一样，NiV在磷酸化蛋白(P)基因的转录过程中使用共转录mRNA编辑来产生额外的编码V和W蛋白的mRNA。C蛋白是从P mRNA翻译过来的，但在另一个阅读框中。体外和体内研究均有证据表明P基因产物在NiV发病机制中起作用。我们开发了一个反向遗传系统来分析NiV P基因产物在限制原代人微血管肺内皮细胞抗病毒反应中的个体作用，这些细胞是人NiV感染的重要靶点。通过对一些重组niv的生长曲线和早期抗病毒反应进行表征，通过基因修饰改变P基因编码蛋白的表达，我们观察到P基因编码的多个元件在调节病毒复制以及限制抗病毒介质（如IFN-β、CXCL10和CCL5）的表达方面具有不同和重叠的作用。我们的发现证实了仓鼠体内感染研究的观察结果，并提供了在感染C、V和w缺陷niv的仓鼠中观察到的衰减和组织病理学的分子见解。本研究的结果也提供了一个机会来验证早期在真实病毒感染背景下的人工质粒表达研究的结果。
Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that causes fatal encephalitis in up to 75% of infected humans. Like other paramyxoviruses, NiV employs co-transcriptional mRNA editing during transcription of the phosphoprotein (P) gene to generate additional mRNAs encoding the V and W proteins. The C protein is translated from the P mRNA, but in an alternative reading frame. There is evidence from both in vitro and in vivo studies to show that the P gene products play a role in NiV pathogenesis. We have developed a reverse genetic system to dissect the individual roles of the NiV P gene products in limiting the antiviral response in primary human microvascular lung endothelial cells, which represent important targets in human NiV infection. By characterizing growth curves and early antiviral responses against a number of recombinant NiVs with genetic modifications altering expression of the proteins encoded by the P gene, we observed that multiple elements encoded by the P gene have both distinct and overlapping roles in modulating virus replication as well as in limiting expression of antiviral mediators such as IFN-β, CXCL10, and CCL5. Our findings corroborate observations from in vivo hamster infection studies, and provide molecular insights into the attenuation and the histopathology observed in hamsters infected with C, V, and W-deficient NiVs. The results of this study also provide an opportunity to verify the results of earlier artificial plasmid expression studies in the context of authentic viral infection.
登录
查看更多内容
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
56.9
作者：
COCCHI, F;DEVICO, AL;LUSSO, P
通讯作者：
LUSSO, P
影响因子：
3.7
作者：
Crameri G;Todd S;Grimley S;McEachern JA;Marsh GA;Smith C;Tachedjian M;De Jong C;Virtue ER;Yu M;Bulach D;Liu JP;Michalski WP;Middleton D;Field HE;Wang LF
通讯作者：
Wang LF
影响因子：
11.8
作者：
Arankalle VA;Bandyopadhyay BT;Ramdasi AY;Jadi R;Patil DR;Rahman M;Majumdar M;Banerjee PS;Hati AK;Goswami RP;Neogi DK;Mishra AC
通讯作者：
Mishra AC
影响因子：
3.7
作者：
Geisbert, Thomas W.;Daddario-DiCaprio, Kathleen M.;Broder, Christopher C.
通讯作者：
Broder, Christopher C.