Regulation of KSHV lytic replication in oral epithelial cells

口腔上皮细胞中 KSHV 裂解性复制的调节

• 批准号: 9099796
• 负责人: Zsolt Toth
• 金额: $ 11.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099796
• 关键词: Acquired Immunodeficiency Syndrome; Adopted; B-Lymphocytes; Bioinformatics; Biology; Characteristics; Chromatin; Complication; Custom; Cytomegalovirus; DNA biosynthesis; Data; Development; Disease; Endothelial Cells; Environment; Epigenetic Process; Epithelial Cells; Euchromatin; Future; Gene Expression Microarray Analysis; Genes; Genetic Transcription; Genome; Gingiva; Goals; Grant; Health; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immunocompromised Host; Individual; Infection; Integration Host Factors; Knowledge; Lead; Libraries; Light; Lytic; Malignant Neoplasms; Molecular; National Institute of Dental and Craniofacial Research; Oncogenic; Oral; Oral cavity; Outcome Study; Palate Kaposi' s Sarcoma; Pathway interactions; Patients; Pilot Projects; Play; Prevention; Primary Infection; Production; Recruitment Activity; Regulation; Reporting; Research Personnel; Role; Saliva; Small Interfering RNA; Structure; Systems Biology; Testing; Vial device; Viral; Viral Genes; Virion; Virus; Virus Replication; base; cell type; design; differential expression; epigenetic drug; high risk; knock-down; lytic gene expression; lytic replication; malignant mouth neoplasm; novel strategies; oral infection; public health relevance; tool; tumorigenesis; viral DNA

 DESCRIPTION (provided by applicant): Recent studies have revealed the importance of the oral environment in the dissemination of Kaposi's sarcoma-associated herpesvirus (KSHV) and the progression to KSHV-associated disease such as oral Kaposi's sarcoma. Oral epithelial cells have been shown to support lytic replication following primary infection and significant amount of transmissible infectious virions have been detected in saliva of KSHV-positive individuals. These studies also suggest that following replication in oral epithelial cells, KSHV may be transmitted into endothelial and B cells where it establishes latency. While latency and lytic reactivation of KSHV in endothelial and B cells have been extensively studied, little is known about the biology of KSHV replication in oral epithelial cells during de novo infection. Thus, the goal of this application is to identify characteristics of oral epithelial cells that predispose them to KSHV replication, which knowledge may help to develop novel strategies for prevention and treatment of oral complication by KSHV infection. We have previously shown that following de novo infection of gingival epithelial cells KSHV adopts a transcriptionally activ chromatin resulting in lytic gene expression and virus replication. Based on our findings we hypothesize that specific host epigenetic factors are recruited to the KSHV genome in oral epithelial cells, which make the viral chromatin permissive for viral transcription resulting in vial replication. In addition, KSHV infection can alter the expression of many cellular genes in oral epithelial cells, which can be critical for the sustained lytic viral replication following de novo infection. Thus, the aim of this pilot study is twofold: (i) to identify critical host epigenetic fctors that control the lytic replication of KSHV in oral epithelial cells, and (ii) to characterize the hst genes specifically altered in oral epithelial cells upon KSHV infection, which can shed light on what makes the oral epithelial cells susceptible for KSHV lytic replication. This NIDCR R03 grant for New Investigators is aimed to establish the preliminary data that is necessary to apply for a larger R01 grant. My future studies will determine the molecular mechanisms of how the identified host epigenetic factors regulate KSHV lytic replication in oral epithelial cells and whether they also play a role in the regulation of lytic reactivation in B cells in which KSHV exists predominantly in latency. Besides KSHV, other human pathogenic herpesviruses (e.g. HSV-1, HCMV, EBV) can also replicate in the oral cavity. Because their lytic replication mechanisms share many similarities with that of KSHV, we will also test whether other oral herpesviruses use the same host epigenetic factors for their replication.

 描述（由申请人提供）：最近的研究揭示了口腔环境在卡波西肉瘤相关疱疹病毒（KSHV）传播和发展为KSHV相关疾病（如口腔卡波西肉瘤）中的重要性。口腔上皮细胞已被证明支持裂解复制后的主要感染和大量的传染性病毒粒子已被检测到唾液中的KSHV阳性的个人。这些研究还表明，在口腔上皮细胞中复制后，KSHV可能被传递到内皮细胞和B细胞中，在那里它建立潜伏期。虽然KSHV在内皮细胞和B细胞中的潜伏期和裂解性再活化已被广泛研究，但对KSHV在口腔上皮细胞中从头感染期间复制的生物学知之甚少。因此，本申请的目标是确定口腔上皮细胞易受KSHV复制的特征，这些知识可能有助于开发预防和治疗KSHV感染口腔并发症的新策略。 我们以前已经表明，在牙龈上皮细胞的从头感染KSHV采用转录活性染色质导致裂解基因表达和病毒复制。基于我们的研究结果，我们假设特定的宿主表观遗传因子被募集到口腔上皮细胞中的KSHV基因组中，这使得病毒染色质允许病毒转录，从而导致小瓶复制。此外，KSHV感染可以改变口腔上皮细胞中许多细胞基因的表达，这对于从头感染后持续的裂解病毒复制至关重要。 感染因此，该初步研究的目的是双重的：（i）鉴定控制KSHV在口腔上皮细胞中裂解复制的关键宿主表观遗传因子，和（ii）表征KSHV感染后口腔上皮细胞中特异性改变的hst基因，这可以阐明是什么使口腔上皮细胞对KSHV裂解复制敏感。 新研究者的NIDCR R 03补助金旨在建立申请更大的R 01补助金所需的初步数据。我未来的研究将确定鉴定的宿主表观遗传因子如何调节KSHV在口腔上皮细胞中裂解性复制的分子机制，以及它们是否也在调节KSHV主要存在于潜伏期的B细胞中的裂解性再活化中发挥作用。除KSHV外，其他人类致病性疱疹病毒（如HSV-1、HCMV、EBV）也可在口腔中复制。由于它们的裂解复制机制与KSHV有许多相似之处，我们还将测试其他口腔疱疹病毒是否使用相同的宿主表观遗传因子进行复制。