Evading innate immunity during human cytomegalovirus latency

在人类巨细胞病毒潜伏期逃避先天免疫

• 批准号: 9919503
• 负责人: ROBERT F KALEJTA
• 金额: $ 35.58万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-02 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919503
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Antiviral Agents; Brain Glioblastoma; Brain Neoplasms; CD8-Positive T-Lymphocytes; CREB1 gene; Cardiovascular Diseases; Cells; Communicable Diseases; Congenital Abnormality; Cytomegalovirus; Cytomegalovirus Infections; Cytotoxic T-Lymphocytes; Data; Detection; Disease; Early Promoters; Elderly; Epigenetic Process; Event; Gene Silencing; Genes; Genetic Transcription; Genome; HIV; Herpesviridae; Heterochromatin; Human; Immune; Immune Evasion; Immunologic Surveillance; Infection; Inflammatory; Innate Immune Response; Invaded; Lead; Life; Link; Lysine; Lytic; Lytic Phase; Maintenance; Malignant Neoplasms; Mediating; Natural Immunity; Organ Transplantation; Pattern recognition receptor; Persons; Phase; Phosphotransferases; Proteins; Publishing; Role; Series; Signal Transduction Pathway; Stimulus; Testing; Time; Viral; Viral Genome; Virus; Virus Latency; Work; activating transcription factor; cytokine; design; ds-DNA; fighting; gene repression; histone methylation; innate immune pathways; pathogen; pathogenic virus; prevent; promoter; reactivation from latency; recruit; response; transcription factor

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.

先天免疫感知细胞内病原体并诱导细胞基因的表达 抗病毒功能。大多数（如果不是全部）病毒都编码在生产、裂解过程中抑制先天免疫的蛋白质。 感染，但病毒潜伏期间先天免疫的作用未被充分认识和研究。 潜伏期使得人类巨细胞病毒 (HCMV) 通过避免免疫而在其宿主的一生中定殖。 检测和清除。在潜伏期，裂解（生产）期 HCMV 蛋白（如 IE1）的水平 （立即早期 1）保持极低（或完全不存在），因为驱动其的启动子 表达时，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，可促进病毒裂解阶段的进展，并且是 细胞毒性T细胞。因此，保持 IE1 蛋白水平较低或不存在可以保护潜伏感染的细胞免受感染。 免疫监视并限制重新激活事件，直到感知到适当的刺激。我们发表了 病毒 UL138 蛋白在潜伏期通过抑制赖氨酸的募集来沉默 IE1 转录 MIEP 的特异性去甲基酶 (KDM) 可去除抑制性表观遗传组蛋白 甲基化来激活转录。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 是如何介导的 细胞先天免疫的逃避有助于 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。