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

• 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
• 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' 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

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 Kaposi的肉瘤相关疱疹病毒（KSHV）是大型DNA病毒，它是几种病因 艾滋病相关的恶性肿瘤，例如卡波西肉瘤，一级积液淋巴瘤和侵略性形式 多中心Castleman病。 KSHV的裂解复制对于KSHV诱导的肿瘤发生和 病毒的传播。最近的研究表明，在口腔上皮细胞中复制后，KSHV 可以传播到内皮和B细胞中，该病毒会建立潜伏期导致持续感染 主持人。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， 这介导了人群中的病毒传播。尽管口腔具有医学和生物学的重要性 KSHV感染，仍然不知道哪种病毒和宿主因素在裂解KSHV的调节中起作用 口腔上皮细胞的感染。 KSHV在编码四个病毒干扰素的人类病毒中是独一无二的 与细胞IRF同源的调节因子。这些病毒蛋白已被证明可以调节许多 不同的免疫相关途径可以增强细胞的生长和细胞存活。虽然其中许多virf 功能与VIRF的细胞质功能有关，VIRF在基因调节中的核作用，尤其是 在口服上皮细胞中，可能促进裂解KSHV感染的细胞仍然很少了解。揭示VIRF的作用 在病毒和细胞基因调节中，我们已经确定了原代人中每个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，我们进行了 从KSHV感染的细胞中VIRF1的蛋白质复合物纯化，发现Virf1可以与 参与DNA结合，组蛋白乙酰化或组蛋白甲基化的几种宿主表观遗传因子。基于 我们的初步数据，该提案的目标是（目标1）识别VIRF的直接目标基因并测试其 在裂解KSHV感染中的作用，以及（AIM 2）研究由VIRF1和 其相关的宿主表观遗传因素，这对于支持KSHV的裂解复制至关重要。自从很多 由VIRF1调节的宿主基因编码在其他病毒感染中被脱离的因子 好吧，我们设想了KSHV期间VIRF1的表观遗传机理和宿主基因靶标的研究 感染可以为新的抗病毒疗法的未来开发提供新的目标。