Evading innate immunity during human cytomegalovirus latency

先天免疫感测细胞内病原体并诱导细胞基因的表达， 抗病毒功能。大多数病毒编码的蛋白质在生产、溶解和免疫过程中抑制先天免疫。 感染，但先天免疫在病毒潜伏期的作用是低估和研究不足。 潜伏期允许人巨细胞病毒（HCMV）通过避免免疫反应而在其宿主中终生定殖。 侦查和清除在潜伏期，裂解期（生产期）HCMV蛋白如IE1 （立即早期1）保持极低（或完全不存在），因为驱动其的启动子 在表达中，主要立即早期启动子（MIEP）被异染色质转录沉默。 IE1是一种转录因子，可促进病毒裂解期的进展，是病毒裂解的靶点。 细胞毒性T细胞因此，保持IE1蛋白水平较低或不存在可保护潜伏感染的细胞免受感染。 免疫监视和限制再激活事件，直到适当的刺激被感知。我们发表了 病毒UL138蛋白通过抑制赖氨酸的募集，在潜伏期期间沉默IE1转录。 MIEP的特异性脱甲基酶（KDM），否则会去除抑制性表观遗传组蛋白 甲基化以激活转录。我们的初步数据表明，这种情况部分是通过 抑制细胞先天免疫途径。在这里，我们建议确定UL138介导的 逃避细胞先天免疫有助于HCMV潜伏期的建立和维持， 特别关注病毒表观遗传学和IE1的转录沉默。

Innate immunity senses intracellular pathogens and induces the expression of cellular genes with antiviral functions. Most if not all viruses encode proteins that inhibit innate immunity during productive, lytic infections, but the role of innate immunity during viral latency is underappreciated and understudied. Latency permits human cytomegalovirus (HCMV) to colonize its hosts for their lifetime by avoiding immune detection and clearance. During latency, the levels of lytic (productive) phase HCMV proteins such as IE1 (Immediate Early 1) are kept extremely low (or completely absent) because the promoter that drives its expression, the Major Immediate Early Promoter (MIEP) is transcriptionally silenced by heterochromatin. IE1 is a transcription factor that promotes progression through the viral lytic phase and is a target of cytotoxic T cells. Therefore, keeping IE1 protein levels low or absent protects latently infected cells from immune surveillance and restricts reactivation events until the proper stimulus is sensed. We published that the viral UL138 protein silences IE1 transcription during latency by inhibiting the recruitment of lysine- specific demethylases (KDMs) to the MIEP that otherwise remove repressive epigenetic histone methylations to activate transcription. Our preliminary data indicates this occurs, in part, through a suppression of cellular innate immune pathways. Here we propose to determine how UL138-mediated evasion of cellular innate immunity contributes to the establishment and maintenance of HCMV latency, with a particular focus on viral epigenetics and the transcriptional silencing of IE1.