Deletion of the Human Cytomegalovirus US17 Gene Increases the Ratio of Genomes per Infectious Unit and Alters Regulation of Immune and Endoplasmic Reticulum Stress Response Genes at Early and Late Times after Infection
Deletion of the Human Cytomegalovirus US17 Gene Increases the Ratio of Genomes per Infectious Unit and Alters Regulation of Immune and Endoplasmic Reticulum Stress Response Genes at Early and Late Times after Infection
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DOI：
10.1128/jvi.02704-13
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发表时间：
2014-02-01
影响因子：
5.4
通讯作者：
Pellett, Philip E.
中科院分区：
文献类型：
--
作者：
Gurczynski, Stephen J.;Das, Subhendu;Pellett, Philip E.
人巨细胞病毒（HCMV）采用多种策略来对抗，破坏或吸收宿主免疫力。其中一种进化策略是捕获宿主基因，然后进行连续复制和分化，形成一个基因家族，其中许多基因具有免疫调节活性。HCMV US12家族由HCMV基因组独特的短（US）区域（US12至US21）中的10个串联排列的序列相关基因组成。每个基因编码的蛋白质具有7个预测的跨膜结构域，补丁的序列相似性与细胞G蛋白偶联受体，和Bax抑制剂1家族的抗凋亡蛋白。我们发现，一个成员，US17，在病毒粒子成熟过程中起着重要的作用。用US17缺失的重组HCMV分离株（Delta US17突变病毒）感染的细胞的微阵列分析显示，感染后早期（感染后12小时[hpi]）宿主先天性和干扰素应答减弱，这与先前在缺乏免疫调节皮层蛋白pp65（pUL83）的情况下观察到的模式相反。尽管Delta US17突变体病毒在成纤维细胞中产生的感染性颗粒数量与亲本病毒产生的数量相等，但它产生的含基因组的非感染性病毒颗粒多3倍，并向新感染的细胞递送更多量的pp65。这些结果表明，US17已经进化为控制病毒体组成，以引起适当平衡的宿主免疫应答。在稍后的时间点（96 hpi），Delta US17突变体感染的细胞显示出几种宿主内质网应激反应基因和分子伴侣的异常表达，其中一些对于病毒体组装和排出的最后阶段是重要的。我们的研究结果表明，US17调节宿主途径，使病毒体的产生，引起适当平衡的宿主免疫反应。
Human cytomegalovirus (HCMV) employs numerous strategies to combat, subvert, or co-opt host immunity. One evolutionary strategy for this involves capture of a host gene and then its successive duplication and divergence, forming a family of genes, many of which have immunomodulatory activities. The HCMV US12 family consists of 10 tandemly arranged sequence-related genes in the unique short (US) region of the HCMV genome (US12 to US21). Each gene encodes a protein possessing seven predicted transmembrane domains, patches of sequence similarity with cellular G-protein-coupled receptors, and the Bax inhibitor 1 family of antiapoptotic proteins. We show that one member, US17, plays an important role during virion maturation. Microarray analysis of cells infected with a recombinant HCMV isolate with a US17 deletion (the Delta US17 mutant virus) revealed blunted host innate and interferon responses at early times after infection (12 h postinfection [hpi]), a pattern opposite that previously seen in the absence of the immunomodulatory tegument protein pp65 (pUL83). Although the Delta US17 mutant virus produced numbers of infectious particles in fibroblasts equal to the numbers produced by the parental virus, it produced>3-fold more genome-containing noninfectious viral particles and delivered increased amounts of pp65 to newly infected cells. These results suggest that US17 has evolved to control virion composition, to elicit an appropriately balanced host immune response. At later time points (96 hpi), Delta US17 mutant-infected cells displayed aberrant expression of several host endoplasmic reticulum stress response genes and chaperones, some of which are important for the final stages of virion assembly and egress. Our results suggest that US17 modulates host pathways to enable production of virions that elicit an appropriately balanced host immune response.