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EPITRANSCRIPTOMIC REGULATION OF CYTOMEGALOVIRUS INFECTION

巨细胞病毒感染的外转录调控

基本信息

批准号：
10578844
负责人：
Daniel Pearce Depledge
金额：
$ 54.54万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578844
关键词：
Address Adenosine Autoimmune Diseases Biological Process Biology Cell Cycle Cells Chemicals Circadian Rhythms Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Data Development Disease Enzymes Eukaryota Fetus Gene Expression Genes Genetic Transcription Human Immune response Immunity Immunocompromised Host Individual Infection Innate Immune Response Interferons Life Mediating Medical Messenger RNA Methylation Methyltransferase Modification Morbidity - disease rate Mothers Natural Immunity Newborn Infant Organ Pathogenesis Perinatal Infection Phosphotransferases Play Positioning Attribute Pregnancy Primary Infection Process Proteins RNA RNA methylation Reader Regulation Reporting Reproduction Role Rubella virus Shapes Signal Pathway Simplexvirus Solid Source Stem cell transplant Testing Therapeutic Intervention Toxoplasma gondii Transplant Recipients Vaccine Design Viral Viral Genes Virus Virus Diseases base biological adaptation to stress congenital cytomegalovirus design ds-DNA epitranscriptomics genomic locus human pathogen maternal morbidity mortality novel therapeutics pathogen prevent recruit response transmission process vaccine development vaccine strategy viral RNA

项目摘要

7. PROJECT SUMMARY / ABSTRACT Chemical modification of mRNA provides a powerful means to dynamically alter gene expression in eukaryotes via epitranscriptomic changes. In particular, methylation of adenosine at the N6 position (m6A) constitutes the most widespread internal base modification to mRNA. Modification of mRNA by m6A influences numerous biological processes including development, differentiation, reprogramming, circadian rhythm, cell cycle, disease pathogenesis, and stress responses including virus infection. Significantly, virus-encoded mRNAs are also chemically modified by m6A, and a role for m6A in Human Cytomegalovirus (HCMV) infection biology is emerging. As a canonical TORCH (T. gondii, other, rubella virus, HCMV, HSV) pathogen, primary HCMV infection during pregnancy remains the leading viral cause of birth defects. While HCMV infection causes mild if any maternal morbidity and is predominately asymptomatic in healthy individuals, it results in life-threatening disease among the immunocompromised, including solid-organ or stem cell transplant recipients, and is a significant source of congenital morbidity and mortality among newborn infants in the developed world. Addressing HCMV congenital infection remains a serious unmet medical need as there is no HCMV vaccine to prevent primary infection during pregnancy and no current treatment to prevent transmission from mother to fetus. Our long-term objective is to understand how the chemical modification of host and/or viral RNA by m6A impacts reproduction of HCMV, a common infection that remains the leading viral cause of congenital abnormalities. Preliminary results demonstrate that cellular m6A methyltransferase subunits METTL3/14, the m6A demethylase ALKBH5, and m6A recognition proteins regulate HCMV reproduction and responses to double strand DNA (dsDNA) in uninfected cells. This is achieved in part through changes in interferon b gene (IFNB1) expression. These findings establish that m6A RNA modification enzymes regulate cellular responses to HCMV and dsDNA sensing, which shapes host immunity and contributes to autoimmune disease. It further suggests that m6A epitranscriptomic changes play a fundamental role in cell-intrinsic innate immune responses to the TORCH pathogen HCMV. Based upon our preliminary results, we hypothesize that HCMV reproduction is differentially controlled by the host m6A modification machinery. Here, this hypothesis will be tested in three specific aims designed to: (i) identify how the host m6A modification machinery is regulated in response to HCMV infection; (ii) determine how cellular m6A modification enzymes regulate IFNB1 mRNA accumulation in HCMV-infected cells; and (iii) identify how HCMV gene expression is impacted by differential m6A modification. The project is significant because it investigates how epitranscriptomic changes impact HCMV reproduction and innate immunity. Understanding how HCMV infection is regulated by epitranscriptomic RNA modification could lead to new opportunities for therapeutic intervention and possibly new strategies for vaccine development.

7. 项目概要/摘要 mRNA 的化学修饰提供了动态改变真核生物基因表达的强大手段通过表观转录组的变化。特别是，N6 位点 (m6A) 的腺苷甲基化构成了最广泛的 mRNA 内部碱基修饰。 m6A 对 mRNA 的修饰影响众多生物过程，包括发育、分化、重编程、昼夜节律、细胞周期、疾病发病机制和应激反应，包括病毒感染。值得注意的是，病毒编码的 mRNA 是也经过 m6A 化学修饰，m6A 在人类巨细胞病毒 (HCMV) 感染生物学中的作用是正在出现。作为典型的 TORCH（弓形虫、其他、风疹病毒、HCMV、HSV）病原体，原发性 HCMV 怀孕期间的感染仍然是导致出生缺陷的主要原因。虽然 HCMV 感染会导致轻度如果任何产妇发病并且健康个体大多无症状，则会导致危及生命免疫功能低下者（包括实体器官或干细胞移植受者）中的疾病，是一种是发达国家新生儿先天性发病和死亡的重要来源。解决 HCMV 先天性感染仍然是一个严重的未满足的医疗需求，因为没有 HCMV 疫苗预防怀孕期间的原发感染，目前尚无治疗方法可以防止母婴传播胎儿。我们的长期目标是了解宿主和/或病毒 RNA 的化学修饰如何 m6A 影响 HCMV 的繁殖，HCMV 是一种常见感染，仍然是导致 HCMV 感染的主要原因先天性异常。初步结果表明细胞 m6A 甲基转移酶亚基 METTL3/14、m6A 去甲基化酶 ALKBH5 和 m6A 识别蛋白调节 HCMV 繁殖和未感染细胞对双链 DNA (dsDNA) 的反应。这部分是通过改变来实现的干扰素b基因（IFNB1）的表达。这些发现证实 m6A RNA 修饰酶调节细胞对 HCMV 和 dsDNA 感应的反应，塑造宿主免疫并有助于自身免疫疾病。它进一步表明 m6A 表观转录组变化在细胞内在先天性中发挥着重要作用对 TORCH 病原体 HCMV 的免疫反应。根据我们的初步结果，我们假设 HCMV 的繁殖受宿主 m6A 修饰机制的差异控制。这里，这个假设将针对三个具体目标进行测试，旨在：（i）确定主机 m6A 修改机制如何针对 HCMV 感染进行调节； (ii) 确定细胞 m6A 修饰酶如何调节 IFNB1 HCMV感染细胞中mRNA的积累； (iii) 确定 HCMV 基因表达如何受到以下因素的影响差分m6A修改。该项目意义重大，因为它研究了表观转录组如何变化影响 HCMV 繁殖和先天免疫。了解 HCMV 感染是如何调节的表观转录组 RNA 修饰可能为治疗干预带来新的机会，并可能疫苗开发的新策略。