IRF-1: a brake to limit gammaherpesvirus infection and pathogenesis

IRF-1：限制伽马疱疹病毒感染和发病机制的刹车

• 批准号: 10066315
• 负责人: Vera L. Tarakanova
• 金额: $ 36.53万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-05 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066315
• 关键词: Adult; Affect; Animal Model; Animals; Apoptosis; Attenuated; B cell differentiation; B-Cell Activation; B-Cell Lymphomas; B-Lymphocytes; Chronic; Communicable Diseases; DNA; Developed Countries; Development; Ensure; Enzymes; Future; Gene Expression; Genetic; Genetic Polymorphism; Goals; HIV/HCV; Helper-Inducer T-Lymphocyte; Hepatitis B Virus; Hodgkin Disease; Human; Human Herpesvirus 4; IRF1 gene; Immune signaling; Immunocompromised Host; Immunology; Incidence; Individual; Infection; Integration Host Factors; Lead; Life; Link; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; Memory B-Lymphocyte; Modeling; Molecular; Pathogenesis; Predisposing Factor; Process; Protein Kinase; Reaction; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Translating; Tumor Suppressor Proteins; Viral; Virus; Virus Diseases; gammaherpesvirus; human disease; insight; novel; patient population; programs; protein kinase C beta; response; transcription factor

PROJECT SUMMARY Gammaherpesviruses establish life-long infection in a majority of humans worldwide and are associated with the development of cancer, including B cell lymphomas. The intimate relationship between gammaherpesviruses and B cell differentiation is directly linked to the lymphomagenic capacity of these viruses. To ensure the establishment of long-term latency in memory B cells, gammaherpesviruses drive a unique polyclonal germinal center reaction during early infection. Germinal center reaction represents a stage of B cell differentiation that is characterized by rapid division of activated B cells along with genetic instability driven by enzymes that either induce DNA breaks or mutagenize DNA. It is not surprising that most Epstein-Barr virus-driven B cell lymphomas originate from germinal center or post germinal center B cells. This robust, gammaherpesvirus-stimulated germinal center reaction is transient and returns to near-baseline levels in long-term infected hosts. Importantly, it is not clear what attenuates gammaherpesvirus-driven germinal center reaction. We have identified Interferon Regulatory Factor-1 (IRF-1) as the first host factor that specifically attenuates gammaherpesvirus-driven germinal center reaction. Studies proposed here test the hypothesis that IRF-1 is the critical host factor that attenuates gammaherpesvirus-driven expansion and transformation of germinal center B cells throughout life-long infection. The proposed studies will define IRF-1-mediated signaling changes that attenuate gammaherpesvirus-driven expansion of germinal center response and the relative contributions of B- and T cell-intrinsic functions of IRF-1 to this process. Further, proposed studies will develop a novel animal model of gammaherpesvirus lymphomagenesis. Successful completion of the proposed studies will offer insights into the tumor suppressor mechanisms of IRF-1 and generate novel animal models that will be of value to infectious disease, immunology, and cancer fields.

项目概要 伽马疱疹病毒在全世界大多数人中造成终生感染，并且 与癌症（包括 B 细胞淋巴瘤）的发展有关。亲密的 伽马疱疹病毒和 B 细胞分化之间的关系直接与 这些病毒的致淋巴瘤能力。确保建立长期延迟 记忆B细胞，伽马疱疹病毒在过程中驱动独特的多克隆生发中心反应 早期感染。生发中心反应代表 B 细胞分化的一个阶段 其特征是激活的 B 细胞快速分裂以及由以下因素驱动的遗传不稳定性 诱导 DNA 断裂或诱变 DNA 的酶。毫不奇怪，大多数 EB 病毒驱动的 B 细胞淋巴瘤起源于生发中心或生发后 中心B细胞。这种强烈的、伽马疱疹病毒刺激的生发中心反应是短暂的 并在长期感染的宿主中恢复到接近基线水平。重要的是，目前还不清楚是什么 减弱伽马疱疹病毒驱动的生发中心反应。我们已经鉴定出干扰素 调节因子-1 (IRF-1) 作为第一个特异性减弱的宿主因子 伽马疱疹病毒驱动的生发中心反应。这里提出的研究测试了假设 IRF-1 是减弱伽马疱疹病毒驱动的扩张的关键宿主因子 生发中心 B 细胞在终生感染过程中的转化。拟议的研究 将定义 IRF-1 介导的信号变化，从而减弱伽玛疱疹病毒驱动的信号变化 生发中心反应的扩展以及 B 细胞和 T 细胞固有的相对贡献 IRF-1在此过程中发挥的作用。此外，拟议的研究将开发一种新型动物模型 伽马疱疹病毒淋巴瘤发生。成功完成拟议的研究将 深入了解 IRF-1 的肿瘤抑制机制并产生新的动物 对传染病、免疫学和癌症领域有价值的模型。

项目成果

T Cell-Intrinsic Interferon Regulatory Factor 1 Expression Suppresses Differentiation of CD4+ T Cell Populations That Support Chronic Gammaherpesvirus Infection.

T 细胞内在干扰素调节因子 1 表达抑制支持慢性伽玛疱疹病毒感染的 CD4 T 细胞群的分化。

• DOI: 10.1128/jvi.00726-21
• 发表时间: 2021
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Jondle,CN;Johnson,KE;Mboko,WP;Tarakanova,VL
• 通讯作者: Tarakanova,VL

Liver X Receptors Suppress Activity of Cholesterol and Fatty Acid Synthesis Pathways To Oppose Gammaherpesvirus Replication.

• DOI: 10.1128/mbio.01115-18
• 发表时间: 2018-07-17
• 期刊: mBio
• 影响因子: 6.4
• 作者: Lange PT;Schorl C;Sahoo D;Tarakanova VL
• 通讯作者: Tarakanova VL

Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection.

• DOI: 10.1038/s41467-018-07492-4
• 发表时间: 2018-11-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Xin G;Zander R;Schauder DM;Chen Y;Weinstein JS;Drobyski WR;Tarakanova V;Craft J;Cui W
• 通讯作者: Cui W

Innate immunity and alpha/gammaherpesviruses: first impressions last a lifetime.

• DOI: 10.1016/j.coviro.2020.07.002
• 发表时间: 2020-10
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: Jondle CN;Tarakanova VL
• 通讯作者: Tarakanova VL

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection.

B 细胞特异性表达共济失调毛细血管扩张突变蛋白激酶促进慢性伽马疱疹病毒感染。

• DOI: 10.1128/jvi.01103-17
• 发表时间: 2017
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Darrah,EricJ;Kulinski,JosephM;Mboko,WadzanaiP;Xin,Gang;Malherbe,LaurentP;Gauld,StephenB;Cui,Weiguo;Tarakanova,VeraL
• 通讯作者: Tarakanova,VeraL