Gammaherpesvirus and IL-17: using host antibacterial defense to benefit chronic virus infection

伽玛疱疹病毒和 IL-17：利用宿主抗菌防御来有益于慢性病毒感染

• 批准号: 10283264
• 负责人: Vera L. Tarakanova
• 金额: $ 21.41万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283264
• 关键词: Adult; Anatomy; Anti-Bacterial Agents; Antibodies; Applications Grants; Automobile Driving; B cell differentiation; B-Cell Lymphomas; B-Lymphocytes; Bacteria; Bacterial Infections; Cells; Chronic; Development; Homologous Gene; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immunoglobulin Somatic Hypermutation; Infection; Interleukin-17; Life; Life Cycle Stages; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Memory; Memory B-Lymphocyte; Modeling; Mus; Mycoses; Pathogenicity; Phenotype; Plasma; Population; Predisposition; Process; Proliferating; Risk; Risk Factors; Role; Saimiriine Herpesvirus 2; Signal Transduction; Structure of germinal center of lymph node; Testing; Time; Viral; Viral reservoir; Virus; Virus Diseases; Virus Latency; antimicrobial; bacterial genetics; base; chronic infection; co-infection; cytokine; gammaherpesvirus; insight; latent infection; novel; novel strategies; pathogenic bacteria; pathogenic fungus; response

Abstract Gammaherpesviruses establish infection in >95% of adults and are associated with multiple cancers, including B cell lymphomas. These viruses usurp B cell differentiation by infecting naïve B cells and driving entry of latently infected and bystander B cells into a germinal center response to ultimately achieve life-long latency in memory B cells. Importantly, the germinal center response is highly mutagenic and is thought to be the target of viral transformation. The mechanisms by which gammaherpesviruses usurp B cell differentiation, including germinal center response, are largely unknown. This proposal is based on our discovery that IL-17A selectively promotes the gammaherpesvirus-driven germinal center response and viral reactivation, two processes that are associated with increased risk of viral lymphomagenesis. IL-17A is induced by and contributes to the clearance of bacterial and fungal pathogens, with our studies revealing an unexpected proviral role of this cytokine. The proposed studies test the hypothesis that natural induction of IL-17A by bacterial pathogens is usurped by gammaherpesviruses to promote germinal center response and viral reactivation. The proposed studies will determine the extent to which a systemic or anatomically restricted bacterial infection impacts gammaherpesvirus-driven germinal center response and viral reactivation and use host and bacterial genetics to define the role of IL-17A in this process. Successful completion of the proposed studies will for the first time define the impact of natural IL-17A induction by common bacterial pathogens on the key pathogenic processes associated with viral lymphomagenesis and will provide insight into novel approaches to target susceptibility to virus-driven lymphomas.

抽象的 γ掌病毒在> 95％的成年人中建立感染，并与多种癌症有关，包括 B细胞淋巴瘤。这些病毒通过感染幼稚的B细胞并驱动进入 潜在感染和旁观者B细胞进入生发中心反应，以最终达到终身潜伏期 记忆B单元。重要的是，生发中心反应是高度诱变的，被认为是目标 病毒转化。 Gammaherpesviruess uturp B细胞分化的机制，包括 生发中心反应在很大程度上未知。该提议是基于我们发现IL-17A的发现 有选择地促进γ掌病毒驱动的生发中心反应和病毒重新激活，两个 与病毒淋巴作用的风险增加有关的过程。 IL-17a由和 有助于清除细菌和真菌病原体，我们的研究表明了出乎意料的 该细胞因子的前病毒作用。提出的研究检验了以下假设 γ掌病毒使用细菌病原体来促进生发中心反应和 病毒重新激活。拟议的研究将确定全身性或解剖学的程度 受限制的细菌感染会影响γ掌病毒驱动的生发中心反应和病毒重新激活 并使用宿主和细菌遗传学来定义IL-17a在此过程中的作用。成功完成 拟议的研究将首次定义自然IL-17A诱导的影响。 与病毒淋巴作用相关的关键致病过程中的病原体，并将提供洞察力 进入针对病毒驱动淋巴瘤易感性的新方法。