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 KSHV 相关疾病（例如口腔卡波西肉瘤）的进展中的重要性。支持初次感染后的裂解性复制，并且在 KSHV 阳性个体的唾液中检测到大量可传播的传染性病毒粒子。这些研究还表明，在复制后。在口腔上皮细胞中，KSHV 可能会传播到内皮细胞和 B 细胞中，并在那里建立潜伏期。虽然 KSHV 在内皮细胞和 B 细胞中的潜伏期和裂解性再激活已被广泛研究，但人们对 KSHV 在口腔上皮细胞中复制的生物学知之甚少。因此，本应用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制定新的预防策略。我们之前已经证明，在牙龈上皮细胞重新感染后，KSHV 采用转录活性染色质，导致裂解基因表达和病毒复制。口腔上皮细胞中的 KSHV 基因组，使病毒染色质允许病毒转录，从而导致小瓶复制。此外，KSHV 感染可以改变许多细胞的表达。口腔上皮细胞中的基因，这对于从头开始后持续裂解病毒复制至关重要 因此，这项初步研究的目的有两个：（i）确定控制口腔上皮细胞中 KSHV 裂解性复制的关键宿主表观遗传因子，以及（ii）特异地表征口腔上皮细胞中的 hst 基因。感染，这可以揭示口腔上皮细胞对 KSHV 裂解性复制敏感的原因。 NIDCR R03 为新研究人员提供的资助旨在建立必要的初步数据。我未来的研究将确定所识别的宿主表观遗传因子如何调节口腔上皮细胞中 KSHV 裂解性复制的分子机制，以及它们是否也在 KSHV 存在的 B 细胞裂解性再激活的调节中发挥作用。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，因为它们的裂解复制机制有许多相似之处。与 KSHV 一样，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。