Immune evasion mechanisms by a tumor herpesvirus in the oral cavity

口腔肿瘤疱疹病毒的免疫逃避机制

基本信息

批准号：
10521292
负责人：
Bernadett Papp
金额：
$ 36.22万
依托单位：
UNIVERSITY OF FLORIDA
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：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521292
关键词：
AIDS related cancer Acetylation Antiviral Therapy B-Lymphocytes Binding Biological Cell Communication Cell Nucleus Cell Survival Cells ChIP-seq Complex Cytoplasm DNA Binding DNA Binding Domain DNA Viruses Data Development Down-Regulation EZH2 gene Endothelium Epigenetic Process Epithelial Cells Epithelium Etiology Future Gene Expression Gene Expression Regulation Gene Targeting Genes Gingiva Goals Herpesviridae Herpesviridae Infections Histone Acetylation Histone H3 Host Defense Human Human Herpesvirus 8 Immune Immune Evasion Immune Response Regulation Pathway Infection Integration Host Factors Investigation Kaposi Sarcoma Knowledge Link Lysine Lytic Lytic Phase Mediating Medical Methylation Multicentric Angiofollicular Lymphoid Hyperplasia Nuclear Oncogenic Viruses Oral cavity Oral mucous membrane structure Palate Kaposi&apos s Sarcoma Pathway interactions Polycomb Population Proteins Regulation Regulator Genes Repression Role Saliva Source Testing Viral Viral Genes Viral Genome Viral Physiology Viral Proteins Viral reservoir Virus Virus Diseases Virus Replication cell growth chronic infection gene induction gene induction/repression gene repression genome-wide histone acetyltransferase histone methylation histone methyltransferase lytic replication mutant novel oral cavity epithelium oral infection particle pathogen primary effusion lymphoma promoter protein complex recruit small hairpin RNA small molecule inhibitor transcriptional reprogramming transcriptome sequencing transmission process tumor tumorigenesis viral interferon regulatory factor viral interferon regulatory factor-1 viral interferon regulatory factor-3 viral transmission

项目摘要

Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV) is large DNA virus, which is the etiological agent of several AIDS-related malignancies such as Kaposi’s sarcoma, primary effusion lymphoma, and aggressive forms of multicentric Castleman’s disease. Lytic replication of KSHV is critical for both KSHV-induced tumorigenesis and dissemination of the virus. Recent studies have shown that following replication in the oral epithelial cells, KSHV can be transmitted into endothelial and B cells where the virus establishes latency resulting persistent infection of the host. Infected oral epithelial cells also serve as the source of new viral particles shedding into the saliva, which mediates the viral transmission in the population. Despite the medical and biological importance of oral KSHV infection, it is still largely unknown what viral and host factors play a role in the regulation of lytic KSHV infection of oral epithelial cells. KSHV is unique among human viruses that it encodes four viral interferon regulatory factors that are homologous to cellular IRFs. These viral proteins have been shown to regulate many different immune-related pathways and can enhance cell growth and cell survival. While many of these vIRF functions are linked to the cytoplasmic functions of vIRFs, the nuclear role of vIRFs in gene regulation, especially in oral epithelial cells, that may promote lytic KSHV infection is still poorly understood. To reveal the role of vIRFs in viral and cellular gene regulation, we have identified the host target genes of each vIRF in primary human gingival epithelial cells and revealed a highly specialized function for each vIRF. In addition, we performed a protein complex purification of vIRF1 from KSHV-infected cells and discovered that vIRF1 can interact with several host epigenetic factors involved in DNA binding, histone acetylation or histone methylation. Based on our preliminary data, the goal of this proposal is (Aim 1) to identify the direct target genes of vIRFs and test their role in lytic KSHV infection, and (Aim 2) to investigate the gene regulatory mechanisms mediated by vIRF1 and its associated host epigenetic factors, which can be critical for facilitating lytic replication of KSHV. Since many of the vIRF1-regulated host genes encode factors that are known to be de-regulated in other viral infections as well, we envision that the investigation of epigenetic mechanisms and host gene targets of vIRF1 during KSHV infection can provide novel targets for future development of new antiviral therapies.

抽象的卡波西肉瘤相关疱疹病毒 (KSHV) 是一种大型 DNA 病毒，是多种疾病的病原体与艾滋病相关的恶性肿瘤，例如卡波西肉瘤、原发性渗出性淋巴瘤和侵袭性淋巴瘤 KSHV 的多中心裂解复制对于 KSHV 诱导的肿瘤发生和发生至关重要。最近的研究表明，KSHV 在口腔上皮细胞中复制后。可以传播到内皮细胞和 B 细胞中，病毒在那里建立潜伏期，从而导致持续感染受感染的口腔上皮细胞也是脱落到唾液中的新病毒颗粒的来源，尽管口腔具有医学和生物学重要性，但它介导了人群中的病毒传播。 KSHV 感染，目前尚不清楚哪些病毒和宿主因素在溶解性 KSHV 的调节中发挥作用感染口腔上皮细胞的KSHV在人类病毒中是独一无二的，它编码四种病毒干扰素。这些病毒蛋白与细胞 IRF 同源，已被证明可以调节许多因子。不同的免疫相关途径，并且可以增强细胞生长和细胞存活。 vIRF 的功能与 vIRF 的细胞质功能、vIRF 在基因调控中的核作用有关，特别是口腔上皮细胞中可能促进溶解性 KSHV 感染的 vIRF 的作用仍知之甚少。在病毒和细胞基因调控方面，我们已经确定了原代人类中每个 vIRF 的宿主靶基因牙龈上皮细胞并揭示了每个 vIRF 的高度专业化功能此外，我们还进行了一项研究。从 KSHV 感染的细胞中纯化 vIRF1 蛋白复合物，发现 vIRF1 可以与一些宿主表观遗传因素涉及 DNA 结合、组蛋白乙酰化或组蛋白甲基化。根据我们的初步数据，该提案的目标是（目标 1）识别 vIRF 的直接靶基因并测试其在裂解性 KSHV 感染中的作用，以及（目标 2）研究 vIRF1 和介导的基因调控机制其相关的宿主表观遗传因素对于促进 KSHV 的裂解复制至关重要。的 vIRF1 调节的宿主基因编码已知在其他病毒感染中失调的因子，例如好吧，我们设想在 KSHV 期间研究 vIRF1 的表观遗传机制和宿主基因靶标感染可以为未来开发新的抗病毒疗法提供新的靶点。