Biology of HHV-8 interactions with host cells

HHV-8 与宿主细胞相互作用的生物学

• 批准号: 6909887
• 负责人: Bala Chandran
• 金额: $ 31.16万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909887
• 关键词: Kaposi' s sarcoma; biological signal transduction; cell adhesion; cell cell interaction; cell membrane; confocal scanning microscopy; electron microscopy; focal adhesion kinase; guanine nucleotide binding protein; guanosinetriphosphatases; host organism interaction; human herpesvirus 8; immunocytochemistry; integrins; intracellular transport; pathologic process; phosphatidylinositol 3 kinase; phosphorylation; polymerase chain reaction; virus infection mechanism

DESCRIPTION (provided by applicant): One of the major determinants of tropism of any virus is the interactions with cell surface molecules and the subsequent entry. The overall objective is to decipher the molecular events of HHV-8 target cell interactions vital for virus entry and infection, and to define the molecular basis for HHV-8's role in the pathogenesis of KS. HHV-8 enters the endothelial, B, and fibroblast cells via endocytosis. HHV-8 binds to the ubiquitous cell surface heparan sulfate (HS)-Iike molecules via its envelope glycoproteins gB and gpK8.1A, interacts with the cell surface alpha3beta1 integrins via its gB, utilizes it as one of the entry receptor, and induces the phosphorylation of integrin-dependent focal adhesion kinase (FAK). Since activation of FAK, Src-family kinases, and other kinases is central to many paradigms of outside-in signaling by integrins, actin assembly and endocytosis, we hypothesize that by its interaction with integrins, HHV-8 takes advantage of the pre-existing FAK and the associated signaling pathways to promote its entry, to deliver its genome into the nucleus and to modulate a cellular state facilitating the infection. Our studies show the activation of key mediators of integrin-induced signal pathways such as FAK, Src, Shc, PI-3K and RhoGTPases by the purified HHV-8. Purified soluble HHV-8 gB also inducted the FAK dependent target cell adhesion, and integrin-dependent FAK-Src-PI-3K-RhoGTPase signal pathways and cytoskeletal rearrangements. In an integrin-FAK-dependent manner, HHV-8 also activated the PI-3K-PKC-delta,-MEK-ERK signal pathway. To test our hypothesis further, the focus of this grant is to define the role of HHV-8-induced key signal mediators such as FAK, Src and PI-3K in HHV-8 entry into the target cells, subsequent movement in the cytoplasm and delivery of viral DNA into the nuclei of infected cells, and two specific aims were formulated: 1.To define the role of HHV-8 induced FAK, Src and PI-3K in the entry of virus into the target cells. 2. To define the role of HHV-8 induced FAK, Src, PI-3K and RhoGTPases in the migration of capsid/tegument in the cytoplasm of the infected cells and in the delivery of viral genome to the nucleus. These studies are significant since they will provide an insight in the biology of HHV-8 interactions with the host cells. Further understanding of HHV-8-cell signaling will broaden our knowledge of HHV-8 related diseases and eventually lead to new anti-HHV-8 agents, and therapeutic agents against KS.

描述（由申请人提供）：任何病毒的偏向主义的主要决定因素之一是与细胞表面分子的相互作用和随后的进入。总体目的是破译HHV-8靶细胞相互作用的分子事件，对病毒进入和感染至关重要，并确定HHV-8在KS发病机理中的作用的分子基础。 HHV-8通过内吞作用进入内皮，B和成纤维细胞。 HHV-8 binds to the ubiquitous cell surface heparan sulfate (HS)-Iike molecules via its envelope glycoproteins gB and gpK8.1A, interacts with the cell surface alpha3beta1 integrins via its gB, utilizes it as one of the entry receptor, and induces the phosphorylation of integrin-dependent focal adhesion kinase (FAK).由于FAK激活，SRC家庭激酶和其他激酶是整合素，肌动蛋白组装和内吞作用的许多室外信号传导范式的关键，我们认为，HHV-8通过其与整合素的相互作用，HHV-8利用了预先存在的FAK和相关的信号传导途径来促进其基因组合的核心，并将其促进其基因组合，并促进了其基因组合，并将其促进了核心。我们的研究表明，通过纯化的HHV-8，整联蛋白诱导的信号途径的关键介体的激活，例如FAK，SRC，SHC，PI-3K和RHOGTPase。纯化的可溶性HHV-8 GB还引起了依赖FAK的靶细胞粘附，并依赖整联蛋白依赖性FAK-SRC-SRC-PI-3K-RHOGTPase信号途径和细胞骨架重排。 HHV-8以整合素-FAK依赖性方式激活了PI-3K-PKC-DELTA，-Mek-erk信号途径。 To test our hypothesis further, the focus of this grant is to define the role of HHV-8-induced key signal mediators such as FAK, Src and PI-3K in HHV-8 entry into the target cells, subsequent movement in the cytoplasm and delivery of viral DNA into the nuclei of infected cells, and two specific aims were formulated: 1.To define the role of HHV-8 induced FAK, Src and PI-3K病毒进入靶细胞。 2。定义HHV-8诱导的FAK，SRC，PI-3K和Rhogtpases在受感染细胞的细胞质中以及病毒基因组传递到细胞核中的Capsid/Tegument迁移中的作用。 这些研究很重要，因为它们将提供与HHV-8与宿主细胞相互作用的生物学的见解。对HHV-8细胞信号的进一步了解将扩大我们对HHV-8相关疾病的了解，并最终导致新的抗HHV-8药物，并针对KS进行治疗剂。