Evading innate immunity during human cytomegalovirus latency

在人类巨细胞病毒潜伏期逃避先天免疫

基本信息

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
项目类别：
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

项目摘要

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）病毒编码在生产性，裂解过程中抑制先天免疫力的蛋白质感染，但是先天免疫在病毒潜伏期中的作用不足和研究了。潜伏期允许人类巨细胞病毒（HCMV）通过避免免疫来定居其宿主一生检测和间隙。在延迟期间，裂解（生产性）相HCMV蛋白（例如IE1）的水平（立即提早1）保持极低（或完全不存在），因为驱动其的启动子表达，主要的早期启动子（MIEP）通过异染色质在转录沉默。 IE1是一种转录因子，可促进通过病毒裂解相促进进展，是细胞毒性T细胞。因此，保持IE1蛋白水平低或不存在可保护受到的受感染细胞免受免疫监视并限制重新激活事件，直到感觉到适当的刺激为止。我们发表了病毒UL138蛋白静止IE1在潜伏期间的转录，通过抑制赖氨酸的募集 MIEP的特定去甲基酶（KDM），否则去除抑制性表观遗传组蛋白甲基化激活转录。我们的初步数据表明，这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介导的如何逃避细胞先天免疫有助于建立和维持HCMV潜伏期，并有特别关注病毒表观遗传学和IE1的转录沉默。