Roles of Nucleotide Metabolic Control in KSHV Persistence

核苷酸代谢控制在 KSHV 持久性中的作用

• 批准号: 8740968
• 负责人: Jae U Jung
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-13 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8740968
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Anabolism; Animal Model; Antiviral Agents; B-Lymphocytes; Binding; Biochemical; Biological Assay; Cells; DNA; DNA Viruses; DNA biosynthesis; Data; Enzymes; Genetic Materials; Genome; Genomics; Health; Hematopoietic; Hematopoietic stem cells; Herpesviridae; Herpesviridae Infections; Host Defense Mechanism; Human; Human Herpesvirus 8; Immune; Immune response; Immune system; Immunocompromised Host; Infection; Interferons; Invaded; Kaposi Sarcoma; Laboratories; Link; Lymphoproliferative Disorders; Lytic; Lytic Phase; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Modeling; Molecular; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; Mutation; Natural Immunity; Neoplasms; Nucleotide Biosynthesis; Nucleotides; Oncogenic; Organ Transplantation; Outcome; Pathogenesis; Patients; Phosphorylation; Phosphotransferases; Production; Recombinants; Regulation; Role; Signal Transduction; Skin; System; Testing; Therapeutic; Thymidine Kinase; Transplant Recipients; Viral; Virion; Virus; Virus Diseases; Work; gammaherpesvirus; in vivo; inhibitor/antagonist; insight; interest; intermolecular interaction; latent infection; latent persistent infection; lytic replication; mouse model; novel; nucleotide analog; nucleotide metabolism; pathogen; polymerization; polypeptide; positional cloning; precursor cell; primary effusion lymphoma; protein complex; reconstitution; research study; stem; tumor; viral DNA; virology; virus host interaction

Kaposi's sarcoma-associated herpesvirus (KSHV) belongs to the lymphotropic gamma herpesviridae. In immunocompromised patients, such as organ transplant recipients and AIDS patients, KSHV infection is invariantly associated with Kaposi's sarcoma, a skin angiogenic neoplasm. Additionally, KSHV is the etiological agent for two rare lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman's disease. The oncogenic potential and relatively ubiquitous infection imposes an eminent health threat worldwide. Understanding fundamental virology and host immune response are two sides of the same coins of KSHV infection and will pave new avenues to treat KSHV-associated malignancies. Innate immunity is the first line of defense against invading pathogens. Recent advances have outlined the framework of signal transduction in mounting host innate immune response. However, the specific functions of key innate immune components, e.g., the IKK-related kinase IKKe, remain contentious. We have recently discovered that the IKKs kinase restricts gamma herpesvirus lytic replication and enables latent/persistent infection. This study proposes to investigate the molecular mechanisms by which the IKKE kinase negates KSHV lytic replication, thereby enabling persistent infection! We will characterize virus-host interactions involving the IKKe kinase (Aim 1), define the regulatory action of IKKs on KSHV lytic replication (Aim 2), and finally assess the roles of IKKe and viral interactions thereof in KSHV persistent infection using a "humanized" mouse model. This proposal entails a powerful reverse genetic system to perturb virus-host interactions and investigate the roles of these interactions in KSHV lytic replication and persistent infection. The application of lytic replicating system and an animal model will identify key interactions and define mutual regulations of in vivo KSHV infection, instructing us on new ways to contain KSHV infection.

卡波西肉瘤相关疱疹病毒（KSHV）属于嗜淋巴细胞γ疱疹病毒科。在免疫功能低下的患者中，如器官移植受者和艾滋病患者，KSHV感染与卡波西肉瘤（一种皮肤血管生成性肿瘤）无关。此外，KSHV是两种罕见的淋巴组织增生性疾病，原发性渗出性淋巴瘤和多中心Castleman病的病原体。潜在的致癌性和相对普遍的感染在世界范围内造成了显著的健康威胁。了解基本病毒学和宿主免疫反应是KSHV感染同一枚硬币的两面，将为治疗KSHV相关恶性肿瘤铺平新的途径。 先天免疫是抵抗病原体入侵的第一道防线。最近的进展概述了信号转导的框架，在安装主机的天然免疫反应。然而，关键先天免疫成分的特定功能，例如，IKK相关激酶IKKe仍然存在争议。我们最近发现IKK激酶限制γ疱疹病毒裂解复制，并使潜伏/持续感染。本研究旨在探讨IKKE激酶抑制KSHV裂解性复制的分子机制，从而使KSHV持续感染成为可能！我们将描述病毒与宿主的相互作用，包括IKKe激酶（目的1），确定IKK对KSHV裂解复制的调节作用（目的2），并最终使用“人源化”小鼠模型评估IKKe及其病毒相互作用在KSHV持续感染中的作用。这一提议需要一个强大的反向遗传系统来干扰病毒-宿主相互作用，并研究这些相互作用在KSHV裂解复制和持续感染中的作用。裂解复制系统和动物模型的应用将确定关键的相互作用，并确定在体内KSHV感染的相互调节，指导我们的新方法来控制KSHV感染。