TRANSMISSION OF HERPES SIMPLEX ACROSS CELL JUNCTIONS

单纯疱疹病毒跨细胞连接的传播

• 批准号: 6376390
• 负责人: David C. Johnson
• 金额: $ 23.26万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376390
• 关键词: Freund's adjuvant; cadherins; cell adhesion molecules; cell cell interaction; glycoproteins; herpes simplex virus 1; immunoelectron microscopy; intercellular connection; intracellular transport; laboratory mouse; laboratory rabbit; ligands; monoclonal antibody; mutant; phenotype; protein structure function; virus infection mechanism; virus protein; virus replication

Herpes simplex viruses (HSV) can spread very efficiently directly from one cell to a neighboring cell, in epithelial and neuronal tissues. The property appears to involve transport of virus particles across cell junctions or contacts made between cells. Viral glycoproteins gE and gI are necessary for efficient spread of HSV between cells but are not required for entry of extracellular virus. Therefore, HSV gE and gI and homologues in other herpesviruses appear to selectively act in cell-to- cell spread and not at the cell surface during entry of extracellular viruses. This the only example of proteins which function in this manner. gE/gI has also been ascribed an IgG-Fc receptor activity, but this property appears to be unrelated to the capacity to facilitate cell-to-cell transmission. We have found that gE/gI localizes specifically to the lateal surfaces of epithelial cells, colocalizing with adherens junctions and being excluded from tight junctions, and is not present on those lateral surfaces of cells not in contact with other cells. This suggests that gE/gI has the capacity to bind to cell junction components so that accumulation at cell junctions occurs. It is my hypothesis that gE/gI binds to cellular ligands concentrated at cell junctions to promote transfer of virus between cells. The objectives of this research are to examine the molecular mechanisms by which HSV spreads from cell-to-cell. We will study the relationship between cell-cell spread and accumulation of gE/gI at cell junctions, whether gE/gI expressed in cells can saturate cell ligands and block cell-cell spread, the role of various cell junction components and cell adhesion molecules (CAMs) in this process, and attempt to identify cellular ligands of gE/gI. These studies should shed light not only on how this virus interacts with cell junctions but also provide valuable new information on the cell biology of cell junctions. The integrity of cell junctions is important to maintain a permeability barrier and also so that the normal course of differentiation and growth regulation are maintained. Loss of CAMs or CAM adaptors occurs during progression to a more malignant phenotype. CAMs or CAM adaptors, e.g. APC, DCC, and cadherins, are known to act as tumor suppressors and their loss leads to a less differentiated and more motile or metastatic phenotype. I expect that our studies of the interactions between HSV and cell junctions will have significance, providing new information on the relationship between specific CAMs and virus spread and a better understanding of how CAMs function in cells and tissues.

单纯疱疹病毒（HSV）可以非常有效地直接从 在上皮和神经元组织中，一个细胞与相邻的细胞相连。 的 一种似乎涉及病毒颗粒跨细胞运输的特性 细胞之间的连接或接触。病毒糖蛋白gE和gI 是HSV在细胞间有效传播所必需的，但不是 细胞外病毒进入所必需的。 因此，HSV gE和gI以及 其他疱疹病毒中的同源物似乎选择性地作用于细胞间， 细胞外基质进入细胞时，细胞扩散，而不是在细胞表面 病毒 这是唯一一个在这个过程中起作用的蛋白质的例子。 方式 gE/gI也被认为具有IgG-Fc受体活性，但 这一属性似乎与促进能力无关 细胞间的传输 我们发现，gE/gI定位于 特别是上皮细胞的外侧表面，共定位 具有粘附连接，并被排除在紧密连接之外， 不存在于不与其它细胞接触的细胞的那些侧表面上 细胞 这表明gE/gI具有与细胞结合的能力， 结组分，从而在细胞结处发生积累。 它 我的假设是gE/gI与细胞配体结合， 细胞连接，以促进细胞间的病毒转移。的 本研究的目的是研究分子机制， HSV在细胞间传播 我们将研究 在细胞间扩散和细胞连接处gE/gI的积累之间， 细胞中表达的gE/gI是否可以使细胞配体饱和并阻断 细胞-细胞扩散，各种细胞连接成分和细胞的作用 粘附分子（CAM）在这个过程中，并试图确定 gE/gI的细胞配体。 这些研究不仅可以揭示 这种病毒如何与细胞连接相互作用， 关于细胞连接的细胞生物学的新信息。 完整性 细胞连接的重要性是保持渗透性屏障， 也使正常的分化过程和生长调节 保持不变。 在进展过程中发生CAM或CAM适配器丢失 转化为恶性表型 CAM或CAM适配器，例如APC、DCC和 钙粘蛋白是已知的肿瘤抑制因子， 分化程度较低和更具运动性或转移性的表型。 我 希望我们对HSV与细胞相互作用的研究 路口将有意义，提供新的信息， 特异性CAMs和病毒传播之间的关系， 了解CAM如何在细胞和组织中发挥作用。