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: 8992680
• 负责人: Zsolt Toth
• 金额: $ 9.54万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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 2016-03-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992680
• 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; Pharmaceutical Preparations; Pilot Projects; Play; Prevention; 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; high risk; 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（由适用提供）：最近的研究揭示了口腔环境在Kaposi肉瘤相关的疱疹病毒（KSHV）的传播中的重要性，以及与KSHV相关疾病（如口腔Kaposi的肉瘤）的发展。已经证明口腔上皮细胞在原发性感染后支持裂解复制，并且在KSHV阳性个体的唾液中检测到了大量的可传染性感染。这些研究还表明，在口腔上皮细胞中复制后，KSHV可能会传播到内皮和B细胞中，并在其确定潜伏期中。虽然内皮和B细胞中KSHV的潜伏期和裂解重新激活已经广泛研究，但对从头感染期间口腔上皮细胞中KSHV复制的生物学知之甚少。这是该应用的目的是确定使其易受KSHV复制的口服上皮细胞的特征，这些知识可能有助于开发新型策略，以通过KSHV感染来预防和治疗口服并发症。我们先前已经表明，在从头感染后，牙龈上皮细胞KSHV采用转录活性染色质，导致裂解基因表达和病毒复制。根据我们的发现，我们假设将特定的宿主表观遗传因子募集到口腔上皮细胞中的KSHV基因组中，这使病毒染色质允许病毒转录，从而导致瓶子复制。另外，KSHV感染可以改变口腔上皮细胞中许多细胞基因的表达，这对于从头开始后持续的裂解病毒复制至关重要 感染。 That, 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. NIDCR R03对新调查人员的拨款旨在建立申请较大R01赠款所需的初步数据。我的未来研究将确定鉴定出宿主表观遗传因子如何调节口腔上皮细胞中KSHV裂解复制的分子机制，以及它们是否还在调节KSHV主要存在延迟中KSHV的B细胞中的裂解重新激活中起作用。除KSHV外，其他人类致病性疱疹病毒（例如HSV-1，HCMV，EBV）也可以在口腔中复制。由于它们的裂解复制机制与KSHV具有许多相似之处，因此我们还将测试其他口服疱疹病毒是否使用相同的宿主表观遗传因子进行复制。