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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：
10392335
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392335
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表达抗病毒功能。大多数病毒(如果不是所有的话)都会编码蛋白质，在繁殖、裂解过程中抑制先天免疫。感染，但先天免疫在病毒潜伏期间的作用没有得到充分的认识和研究。潜伏期允许人类巨细胞病毒(HCMV)通过避免免疫来终生定植宿主检测和清除。在潜伏期，裂解(生产)阶段的HCMV蛋白水平，如IE1 (即刻早期1)保持极低(或完全不存在)，因为推动其表达，主要的即时早期启动子(MIEP)是转录沉默的异染色质。 IE1是一种转录因子，在病毒裂解阶段促进进展，是细胞毒T细胞。因此，保持低IE1蛋白水平或不保持IE1蛋白水平可保护潜伏感染细胞免疫监视，并限制重新激活事件，直到感觉到适当的刺激。我们发表了那篇文章病毒UL138蛋白通过抑制赖氨酸的募集而在潜伏期沉默IE1的转录。 MIEP的特异性去甲基酶(KDM)，否则会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，这在一定程度上是通过抑制细胞的先天免疫途径。在这里，我们建议确定UL138介导的逃避细胞先天免疫有助于建立和维持HCMV潜伏期，特别关注病毒表观遗传学和IE1的转录沉默。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NFκB and Cyclic AMP Response Element Sites Mediate the Valproic Acid and UL138 Responsiveness of the Human Cytomegalovirus Major Immediate Early Enhancer and Promoter.

NFκB 和环 AMP 反应元件位点介导人类巨细胞病毒主要立即早期增强子和启动子的丙戊酸和 UL138 反应性。

DOI：
10.1128/jvi.00029-23
发表时间：
2023
期刊：
Journal of virology
影响因子：
5.4
作者：
Albright,EmilyR;Walter,RyanM;Saffert,RyanT;Kalejta,RobertF
通讯作者：
Kalejta,RobertF

Human Cytomegalovirus UL138 Protein Inhibits the STING Pathway and Reduces Interferon Beta mRNA Accumulation during Lytic and Latent Infections.

DOI：
10.1128/mbio.02267-21
发表时间：
2021-12-21
期刊：
mBio
影响因子：
6.4
作者：
Albright ER;Mickelson CK;Kalejta RF
通讯作者：
Kalejta RF

Human Cytomegalovirus Genomes Survive Mitosis via the IE19 Chromatin-Tethering Domain.

DOI：
10.1128/mbio.02410-20
发表时间：
2020-09-29
期刊：
mBio
影响因子：
6.4
作者：
Lyon SM;Yetming KD;Paulus C;Nevels M;Kalejta RF
通讯作者：
Kalejta RF

The Golgi sorting motifs of human cytomegalovirus UL138 are not required for latency maintenance.

人巨细胞病毒 UL138 的高尔基体分选基序不需要维持潜伏期。

DOI：
10.1016/j.virusres.2019.197646
发表时间：
2019
期刊：
Virus research
影响因子：
5
作者：
Gelbmann,ChristopherB;Kalejta,RobertF
通讯作者：
Kalejta,RobertF

Human cytomegalovirus lytic infection inhibits replication-dependent histone synthesis and requires stem loop binding protein function.

DOI：
10.1073/pnas.2122174119
发表时间：
2022-04-05
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Albright, Emily R.;Morrison, Kylee;Ranganathan, Padhma;Carter, Dominique M.;Nishikiori, Masaki;Lee, Jeong-Hee;Slayton, Mark D.;Ahlquist, Paul;Terhune, Scott S.;Kalejta, Robert F.
通讯作者：
Kalejta, Robert F.