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.

项目摘要 伽马广播病毒在全球大多数人中建立了终身感染，并且是 与包括B细胞淋巴瘤在内的癌症发展有关。亲密 γ掌病毒与B细胞分化之间的关系直接与 这些病毒的淋巴细胞生成能力。确保建立长期延迟 记忆B细胞，γ掌病毒在期间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 以快速分裂活化的B细胞以及遗传不稳定性的特征 诱导DNA断裂或诱变DNA的酶。大多数人都不奇怪 爱泼斯坦 - 巴尔病毒驱动的B细胞淋巴瘤起源于生发中心或生发后 中心B细胞。这种坚固的，γ掌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的水平。重要的是，尚不清楚什么 减弱γ掌病毒驱动的生发中心反应。我们已经确定了干扰素 调节因子-1（IRF-1）是第一个特别减弱的宿主因素 γ掌病毒驱动的生发中心反应。这里提出的研究检验了假设 IRF-1是减弱γ掌病毒驱动的扩张和的关键宿主因素 在整个终生感染过程中，生发中心B细胞的转化。提出的研究 将定义IRF-1介导的信号传导变化，从而减弱γ掌病毒驱动 生发中心反应的扩展以及B-和T细胞中心的相对贡献 IRF-1在此过程中的功能。此外，拟议的研究将开发一种新型的动物模型 γ掌病毒淋巴作用。成功完成拟议的研究将 提供有关IRF-1肿瘤抑制机制的见解，并产生新型动物 对于传染病，免疫学和癌症领域具有价值的模型。

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