Gammaherpesvirus protein kinase: a master manipulator of the host during chronic infection.

伽玛疱疹病毒蛋白激酶：慢性感染期间宿主的主要操纵者。

• 批准号: 10651854
• 负责人: Vera L. Tarakanova
• 金额: $ 53.49万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-22 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651854
• 关键词: Address; Adult; African Burkitt' s lymphoma; Animal Model; Antiviral Agents; Applications Grants; B cell differentiation; B-Cell Lymphomas; B-Lymphocytes; Cell Compartmentation; Chronic; Cyclic AMP-Dependent Protein Kinases; Development; Ensure; Epstein-Barr Virus Infections; Epstein-Barr Virus-Related Lymphoma; Gene Expression; Genetic; Goals; Heart; Herpesviridae; Herpesviridae Infections; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Infection; Interferons; Interleukin-10; Lead; Life Cycle Stages; Link; Lymphoma; Lymphomagenesis; Lytic; Macrophage; Malignant Neoplasms; Memory B-Lymphocyte; Modeling; Molecular; Mus; Myelogenous; Natural Immunity; Pathogenesis; Pathway interactions; Phenotype; Phosphotransferases; Physiological; Population; Predisposing Factor; Prevention; Proliferating; Protein Kinase; Protein Kinase Interaction; Publishing; Reaction; Risk Factors; Rodent; Role; STAT1 gene; Signal Pathway; Signal Transduction; Species Specificity; Structure of germinal center of lymph node; T cell response; Testing; Transgenic Animals; Vaccines; Viral; Viral Pathogenesis; Viral Physiology; Viral Proteins; Virus; Virus Latency; cell type; chronic infection; gammaherpesvirus; humanized mouse; large cell Diffuse non-Hodgkin' s lymphoma; latent gene expression; latent infection; monocyte; mouse model; new therapeutic target; novel; pathogen; protein function; response; therapeutic target

Gammaherpesviruses establish life-long infections in >95% of adults worldwide and are associated with B cell lymphomas. Prevention of gammaherpesvirus-driven lymphomas is currently impossible due to absence of vaccines, curative antivirals, and defined risk factors for lymphomagenesis. All gammaherpesviruses encode a protein kinase, a key determinant of chronic infection and pathogenesis. This grant application aims to define the molecular and cellular mechanisms underlying physiologically relevant functions of gammaherpesvirus protein kinases during chronic infection of an intact host. Based on our published and preliminary findings, the proposed studies test the working model that macrophage- intrinsic IFN signaling is antagonized by an enzymatically active viral protein kinase to promote the passage of the virus from myeloid to B cell compartment. Once viral access to B cells is gained, viral kinase supports latent viral gene expression and engages host mechanisms to drive B cell differentiation and establishment of chronic infection. Successful completion of the proposed studies will define molecular and cellular mechanisms underlying functions of the conserved gammaherpesvirus protein kinase during chronic infection of an intact natural host. Such mechanisms are likely to operate during viral lymphomagenesis and may present novel therapeutic targets for the prevention of gammaherpesvirus-driven lymphomas.

伽玛疱疹病毒在全球 95% 以上的成年人中造成终生感染，并与乙型疱疹病毒相关 细胞淋巴瘤。由于以下原因，目前不可能预防伽玛疱疹病毒驱动的淋巴瘤 缺乏疫苗、治疗性抗病毒药物和明确的淋巴瘤发生危险因素。全部 伽马疱疹病毒编码蛋白激酶，这是慢性感染和发病机制的关键决定因素。 该拨款申请旨在定义生理学基础的分子和细胞机制 完整宿主慢性感染期间伽马疱疹病毒蛋白激酶的相关功能。基于 我们发表的初步研究结果，拟议的研究测试了巨噬细胞的工作模型 内在的 IFN 信号传导被酶活性病毒蛋白激酶拮抗，以促进通过 病毒从骨髓到 B 细胞室的过程。一旦病毒进入 B 细胞，病毒激酶 支持潜伏病毒基因表达并参与宿主机制驱动 B 细胞分化和 慢性感染的建立。成功完成拟议的研究将定义分子和 慢性期保守的伽玛疱疹病毒蛋白激酶功能的细胞机制 完整自然宿主的感染。这种机制可能在病毒性淋巴瘤发生过程中发挥作用 并可能为预防伽玛疱疹病毒驱动的淋巴瘤提供新的治疗靶点。