Changes in the Cornified Cell Envelope in HPV Infection

HPV 感染时角质化细胞包膜的变化

• 批准号: 7047882
• 负责人: DARRON R BROWN
• 金额: $ 21.58万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047882
• 关键词: athymic mouse; cell membrane; enzyme inhibitors; enzyme substrate; epithelium; genetic transcription; human papillomavirus; human tissue; membrane proteins; protein glutamine gamma glutamyltransferase; tissue mosaicism; virus cytopathogenic effect; virus protein; xenotransplantation

DESCRIPTION (provided by applicant): The mechanism of HPV transmission at the cellular level is poorly understood. Keratinocytes are the target cells for HPV infection. These cells normally exit the cell cycle and undergo the process of differentiation, including expression of proteins that become components of the cornified cell envelope (CCE). Loricrin, involucrin, small proline rich proteins (SPRs), cytokeratins, and other proteins are covalently cross-linked to make up the CCE. The endpoint of differentiation is a layer of flattened, durable, enucleated CCEs that provides the host with barrier protection. HPV infection does not induce cell lysis, and the mechanism of virion escape from infected keratinocytes is not known. The CCE in its normal, durable state would likely hinder virion release. We theorized that a defective CCE would facilitate release of virions. Our studies support this hypothesis. We have shown that HPV 11 infection induces abnormalities of CCEs, and that desquamated, cornified cells from HPV 11 infected tissue are effective transmitters of infection. We have also shown that the HPV 11 El^E4 protein is associated in vivo with the CCE. Our studies of the effects of HPV 11 infection on the CCE demonstrate a markedly reduced amount of Ioricrin and an abundance of SPR3 in HPV 11-infected epithelium. Our studies, performed on fully differentiated epithelium, suggest that HPV 11 gene products cause the defects in the CCE. In addition, our recent studies show that HPV 11 infection reduces Ioricrin transcription. The combined effects of HPV gene products on the CCE may facilitate the escape of virions, and thus increase the efficiency of HPV transmission. In the current proposal, we will test the hypothesis that HPV 11 induces defects of the CCE, and that these defects can be attributed to the effects of the El^E4 and E2 proteins. To test the hypothesis, we will 1) determine if the El^E4 protein is a TGase substrate or an inhibitor of these enzymes; 2) analyze the effects of El^E4 proteins on the composition and biophysical characteristics of CCEs, and 3) examine of the effects of the E2 on expression of the CCE proteins Ioricrin and small proline rich protein 3.

描述（由申请人提供）： HPV 在细胞水平上的传播机制尚不清楚。角质形成细胞是HPV感染的靶细胞。这些细胞通常退出细胞周期并经历分化过程，包括表达成为角化细胞包膜 (CCE) 成分的蛋白质。兜甲蛋白、外皮蛋白、富含脯氨酸的小蛋白 (SPR)、细胞角蛋白和其他蛋白通过共价交联形成 CCE。分化的终点是一层扁平、耐用、去核的 CCE，为宿主提供屏障保护。 HPV 感染不会引起细胞裂解，并且病毒颗粒从受感染的角质形成细胞中逃逸的机制尚不清楚。 CCE 处于正常、持久状态可能会阻碍病毒颗粒的释放。我们推测，有缺陷的 CCE 将促进病毒粒子的释放。我们的研究支持这一假设。我们已经证明，HPV 11 感染会诱导 CCE 异常，并且 HPV 11 感染组织中脱落的角化细胞是有效的感染传播者。我们还表明，HPV 11 E1^E4 蛋白在体内与 CCE 相关。我们对 HPV 11 感染对 CCE 影响的研究表明，在 HPV 11 感染的上皮细胞中，Ioricrin 的量显着减少，而 SPR3 的含量却丰富。我们对完全分化的上皮进行的研究表明，HPV 11 基因产物导致 CCE 缺陷。此外，我们最近的研究表明，HPV 11 感染会降低 Ioricrin 转录。 HPV基因产物对CCE的综合作用可能会促进病毒粒子的逃逸，从而提高HPV传播的效率。在当前的提案中，我们将检验以下假设：HPV 11 诱导 CCE 缺陷，并且这些缺陷可归因于 E1^E4 和 E2 蛋白的作用。为了检验这个假设，我们将 1) 确定 El^E4 蛋白是否是 TGase 底物或这些酶的抑制剂； 2)分析E1^E4蛋白对CCE的组成和生物物理特性的影响，以及3)检查E2对CCE蛋白Ioricrin和富含脯氨酸的小蛋白3的表达的影响。