Factors Influencing KSHV Infection and Spread within the Oral Cavity

影响 KSHV 口腔内感染和传播的因素

• 批准号: 9420193
• 负责人: Jennifer E Totonchy
• 金额: $ 24.9万
• 依托单位: CHAPMAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9420193
• 关键词: Acquired Immunodeficiency Syndrome; Affect; B-Cell Lymphomas; B-Lymphocytes; Biological; Biological Models; Biology; CASP8 and FADD-like apoptosis regulating protein; Cell Line; Cell physiology; Cells; Cellular biology; Complement; Data; Disease; Disease Progression; Endothelial Cells; Epithelial Cells; Etiology; Fibrinogen; Fibroblasts; Foundations; Future; Gene Proteins; Genes; Goals; HIV; HIV Infections; Hand; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 8; Immune; Immune System Diseases; Immune System and Related Disorders; Impairment; In Vitro; Incidence; Individual; Infection; Investigation; Kaposi Sarcoma; Link; Lymphoma; Lymphoproliferative Disorders; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular Genetics; Molecular Virology; Morbidity - disease rate; Mucous Membrane; Multicentric Angiofollicular Lymphoid Hyperplasia; NF-kappa B; Natural History; Oncogenes; Oncogenic; Oral; Oral Manifestations; Oral cavity; Oral mucous membrane structure; Organ Culture Techniques; Palate Kaposi' s Sarcoma; Patients; Persons; Phase; Physiological; Play; Predisposition; Process; Production; Property; Proteins; Publishing; Recombinants; Research; Role; Saliva; Simian B disease; Site; Skin; Solid; Source; Specificity; Structure; System; Techniques; Tissues; Tonsil; Training; Transplant Recipients; Viral; Viral Physiology; Virion; Virus; Virus Diseases; Virus Replication; Viscera; career; career development; cell type; cellular targeting; co-infection; experience; gain of function; gene product; innovation; insight; loss of function; mortality; mutant; new technology; novel; outcome forecast; pathogen; prevent; primary effusion lymphoma; public health relevance; targeted treatment; therapeutic target; tool; transmission process; tumor; tumor progression; tumorigenesis; virology

 DESCRIPTION (provided by applicant): Kaposi sarcoma herpesvirus (KSHV) is an oncogenic human herpesvirus, which causes Kaposi sarcoma (KS) as well as B cell lymphomas in the absence of adequate immune control. KSHV-associated tumors are a significant cause of morbidity and mortality in transplant patients and individuals with HIV-disease. The oral cavity is an important site for KSHV replication and persistence and saliva is believed to be a critical source of person-to-person transmission. Moreover, oral manifestation of KS is associated with rapid progression and high mortality rates. KSHV-associated tumors are multi-focal and frequently polyclonal, suggesting that continued viral infection is important for disease progression. Because of technical challenges unique to KSHV molecular virology, little is known about infection of physiologically relevant cell types. The current project will leverage new molecular genetics tools to explore the fundamental virology of KSHV infection with the goal of identifying novel viral and cellular targets to prevent viral spread and KS progression within the oral cavity. During the K99 phase, we will establish systems for de novo infection of KSHV-susceptible cell types and tissues in order to explore the cell type-specific properties of infectin, persistence and spread. We will then utilize these models to explore the contribution of the viral FLICE- inhibitory protein (vFLIP) in the context of KSHV infection. In order to place these studies in the most disease-relevant context possible, we will include HIV co-infection, as appropriate, to determine fundamental interactions between these two pathogens. With critical training and career development accomplished, model systems in hand, and the vFLIP studies as proof-of-principle for the use of recombinant KSHV strains within these models, I will move forward in the R00 phase to examine the contribution of virion-associated non-structural KSHV proteins to the earliest stages of infection in relevant cell types. These packaged, non-structural proteins comprise a virion structure known as the tegument. Tegument factors affect profound alterations in host cell physiology immediately upon virus entry and studies of these factors in other herpesvirus systems have yielded important insights into viral and cellular biology. However, the composition and function of the KSHV tegument remains obscure and represents a large gap in our understanding of fundamental KSHV virology. The results of this research will provide critical information about the dynamic process of KSHV persistence in the oral cavity and provide insights into both viral and cellular mechanisms that can be exploited for new treatment paradigms. Using a broad but systematic workflow of study for multiple KSHV tegument factors, I will obtain a significant body of both publishable data and preliminary data for multiple future studies that will provide a solid foundation upon which to build an independent research career.

 描述（由适用提供）：Kaposi肉瘤疱疹病毒（KSHV）是一种致癌的人疱疹病毒，在没有足够的免疫对照的情况下会导致Kaposi肉瘤（KS）以及B细胞淋巴瘤。 KSHV相关的肿瘤是移植患者和HIV疾病患者发病率和死亡率的重要原因。口腔是 KSHV复制和持久性和唾液的重要地点被认为是人与人传播的关键来源。此外，KS的口服表现与快速发展和高死亡率有关。 KSHV相关的肿瘤是多焦点且经常多克隆的，这表明持续的病毒感染对于疾病进展很重要。由于KSHV分子病毒学所独有的技术挑战，关于物理相关细胞类型的感染知之甚少。当前的项目将利用新的分子遗传学工具来探索KSHV感染的基本病毒学，目的是识别新型的病毒和细胞靶标，以防止口腔内的病毒扩散和KS进展。在K99阶段，我们将建立用于从头感染KSHV敏感的细胞类型和组织的系统，以探索感染，持久性和扩散的细胞类型特异性。然后，我们将利用这些模型来探索在KSHV感染的情况下，在KSHV感染的背景下，病毒果定抑制蛋白（VFLIP）的贡献。为了将这些研究置于可能的疾病中，我们将在适当的情况下包括HIV共同感染，以确定这两种病原体之间的基本相互作用。随着批判性的培训和职业发展，手头模型系统以及VFLIP研究是在这些模型中使用重组KSHV菌株的原则证明，我将在R00阶段继续前进，以研究与病毒相关的非结构KSHV蛋白的贡献，以期在相关细胞类型的最早感染中。这些包装的，非结构性的 蛋白质包括一个称为团队的病毒结构。病毒进入后立即影响宿主细胞生理的深刻变化，对其他疱疹病毒系统中这些因素的研究产生了对病毒和细胞生物学的重要见解。但是，KSHV技术的组成和功能仍然晦涩难懂，这在我们对基本KSHV病毒学的理解中构成了很大的差距。这项研究的结果将提供有关口腔中KSHV持久性动态过程的关键信息，并提供有关病毒和细胞机制的见解，可以探索新的治疗范式。使用广泛但系统的研究工作流程为多个KSHV团队因素，我将获得可发布的数据和初步数据的重要组件，用于多个将来的研究 研究职业。