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

基本信息

  • 批准号:
    9099796
  • 负责人:
  • 金额:
    $ 11.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

 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(申请人提供):最近的研究揭示了口腔环境在Kaposi肉瘤相关疱疹病毒(KSHV)传播和发展为KSHV相关疾病(如口腔Kaposi肉瘤)中的重要性。口腔上皮细胞被证明支持原发感染后的裂解复制,在KSHV阳性患者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,在口腔上皮细胞复制后,KSHV可能会传播到内皮细胞和B细胞,在那里它建立了潜伏期。虽然KSHV在内皮细胞和B细胞中的潜伏期和裂解再激活已被广泛研究,但对KSHV在口腔上皮细胞新感染过程中的复制生物学知之甚少。因此,这项应用的目的是确定口腔上皮细胞的特性,使其易于复制KSHV,这一知识可能有助于开发预防和治疗KSHV感染引起的口腔并发症的新策略。我们以前已经证明,在牙龈上皮细胞从头感染后,KSHV采用转录激活的染色质,导致裂解基因的表达和病毒的复制。根据我们的发现,我们假设特定的宿主表观遗传因子被招募到口腔上皮细胞的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,这对于从头开始的持续裂解病毒复制是至关重要的。 感染。因此,这项先导性研究的目的有两个:(I)确定控制KSHV在口腔上皮细胞裂解复制的关键宿主表观遗传因子;(Ii)鉴定KSHV感染后口腔上皮细胞中特异改变的hst基因,从而阐明是什么使口腔上皮细胞对KSHV裂解复制易感。NIDCRR03新调查员拨款旨在建立申请更大的R01拨款所需的初步数据。我未来的研究将确定已确定的宿主表观遗传因素如何调控口腔上皮细胞中KSHV裂解复制的分子机制,以及它们是否也在KSHV主要以潜伏期存在的B细胞中的裂解再激活调节中发挥作用。除KSHV外,其他人类致病疱疹病毒(如HSV-1、HCMV、EBV)也可在口腔内复制。由于它们的裂解复制机制与KSHV有许多相似之处,我们也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。

项目成果

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Zsolt Toth其他文献

Zsolt Toth的其他文献

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{{ truncateString('Zsolt Toth', 18)}}的其他基金

Viral and host strategies for regulation of KSHV infection
KSHV 感染调节的病毒和宿主策略
  • 批准号:
    10165473
  • 财政年份:
    2018
  • 资助金额:
    $ 11.25万
  • 项目类别:
Viral and host strategies for regulation of KSHV infection
KSHV 感染调节的病毒和宿主策略
  • 批准号:
    10396062
  • 财政年份:
    2018
  • 资助金额:
    $ 11.25万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 11.25万
  • 项目类别:

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