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: 10518464
• 负责人: Vera L. Tarakanova
• 金额: $ 54.89万
• 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/10518464
• 关键词: Address; Adult; 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; Gene Expression; Genetic; Goals; Heart; Herpesviridae Infections; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Infection; Interferons; Interleukin-10; Lead; Life; Life Cycle Stages; Link; Lymphoma; Lymphomagenesis; Lytic; Malignant Neoplasms; Memory B-Lymphocyte; Modeling; Molecular; Mus; Myelogenous; Natural Immunity; Pathogenesis; Pathway interactions; Phenotype; Phosphotransferases; Physiological; Population; Predisposing Factor; Prevention; Protein Kinase; Publishing; Reaction; Risk Factors; Rodent; Role; STAT1 gene; Signal Pathway; Signal Transduction; Species Specificity; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Transgenic Animals; Vaccines; Viral; Viral Pathogenesis; Viral Physiology; Viral Proteins; Virus; Virus Latency; base; cell type; chronic infection; gammaherpesvirus; humanized mouse; large cell Diffuse non-Hodgkin' s lymphoma; latent gene expression; latent infection; macrophage; 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.

伽马广播病毒在全球> 95％的成年人中建立了终身感染，并且与B相关 细胞淋巴瘤。由于目前无法 缺乏疫苗，治愈性抗病毒药和淋巴作用的危险因素。全部 γ掌病毒编码蛋白激酶，这是慢性感染和发病机理的关键决定因素。 该赠款应用旨在在生理上定义分子和细胞机制 完整宿主的慢性感染过程中γ掌病毒蛋白激酶的相关功能。基于 我们发表的初步发现，拟议的研究测试了巨噬细胞的工作模型 固有的IFN信号传导通过酶活性病毒蛋白激酶拮抗以促进通道 从髓样到B细胞室的病毒。一旦获得了对B细胞的访问，病毒激酶 支持潜在病毒基因表达并参与宿主机制以驱动B细胞分化和 建立慢性感染。成功完成拟议的研究将定义分子和 慢性期间保守的γ掌病毒蛋白激酶的细胞机制 完整天然宿主的感染。这种机制可能在病毒淋巴作用期间起作用 并可能提出了预防γ掌病毒驱动淋巴瘤的新型治疗靶标。