Not just acute: IRF-7 has two site-specific functions against chronic gammaherpesvirus infection

不仅仅是急性：IRF-7 具有两种针对慢性伽马疱疹病毒感染的位点特异性功能

• 批准号: 9979627
• 负责人: Kaitlin E Johnson
• 金额: --
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-11 至 2020-07-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979627
• 关键词: Acute; Animal Model; Antiviral Agents; Antiviral Response; Attenuated; B-Lymphocytes; Cells; Chronic; Development; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Exhibits; Frequencies; Greater sac of peritoneum; High Prevalence; Human; Human Herpesvirus 4; Human Herpesvirus 8; IFNAR1 gene; Immunocompetent; Immunocompromised Host; Individual; Infection; Integration Host Factors; Interferon Receptor; Interferon Type I; Interferons; Lead; Lymphoma; Lytic; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Murine herpesvirus 68; Mus; Oncogenic; Pathogenesis; Peritoneal; Peritoneum; Phenotype; Process; Proteins; Regulation; Risk Factors; Role; Signal Transduction; Site; Species Specificity; Spleen; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Viral; Viral Load result; Viral reservoir; Virus; Virus Diseases; Virus Latency; base; cell type; cellular targeting; chronic infection; defined contribution; experimental study; gammaherpesvirus; in vivo; insight; interferon regulatory factor-7; lytic replication; metaplastic cell transformation; novel therapeutics; pathogen; response; therapeutic target; transcription factor; transmission process; tumorigenesis; virus development

Proposal Summary Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections and are defined by distinct lytic and latent lifecycles. Importantly, human gammaherpesviruses promote a variety of cancers in both immunocompetent and immunocompromised hosts. While risk factors for these virus-driven cancers are poorly understood, it is clear that robust virus-driven germinal center expansion, as well as reactivation of the virus from latency precedes viral oncogenesis. Therefore, host factors that restrict these two processes during infection may represent potential therapeutic targets. Due to the high prevalence and tremendous species specificity of human gammaherpesviruses, the mouse pathogen murine herpesvirus 68 (MHV68) is widely utilized as the small animal model of gammaherpesvirus pathogenesis. A particular strength of this model is the ability to genetically modify the host to examine the cellular and molecular mechanism by which infection is controlled. With this model we have recently identified new and exciting function of the previously underappreciated host factor IRF-7 during gammaherpesvirus infection. Specifically, we found that IRF-7 restricts gammaherpesvirus-driven germinal center expansion at 16 days post infection. Additionally, we found that in the absence of IRF-7, MHV68 reactivates to a greater frequency from peritoneal cells compared to WT. This phenotype was not observed in the spleen. We hypothesize that IRF-7 mediates independent antiviral functions in two separate sites within the host. The in vivo experiments proposed here will provide an extensive, yet focused analysis of the cellular and molecular importance of IRF-7 expression in both the spleen and peritoneal cavity of the host during gammaherpesvirus infection. Importantly, successful completion of these studies will provide insight into the control of gammaherpesvirus infections, which would offer potential therapeutic targets for infected individuals particularly susceptible to the associated oncogenic effects of gammaherpesviruses.

提案摘要 γ疱疹病毒是普遍存在的病原体，其建立终身感染，并由不同的 裂解和潜伏的生命周期。重要的是，人类γ-疱疹病毒在两种组织中促进多种癌症， 免疫活性和免疫受损宿主。虽然这些病毒驱动的癌症的风险因素很差， 理解，很明显，强大的病毒驱动的生发中心扩张，以及病毒的重新激活， 病毒致癌前的潜伏期因此，限制这两个过程的宿主因素 感染可能是潜在的治疗靶点。 由于人γ疱疹病毒的高流行率和巨大的物种特异性，小鼠 病原体鼠疱疹病毒68（MHV 68）被广泛用作γ疱疹病毒的小动物模型 发病机制该模型的一个特别优点是能够对宿主进行遗传修饰，以检查宿主的免疫功能。 控制感染的细胞和分子机制。通过这个模型，我们最近发现 以前未被重视的宿主因子IRF-7在γ疱疹病毒感染中的新的令人兴奋的功能 感染具体来说，我们发现IRF-7限制了γ疱疹病毒驱动的生发中心在16 感染后的天数。此外，我们发现，在缺乏IRF-7的情况下，MHV 68重新激活到更高的水平。 与WT相比，来自腹膜细胞的频率。在脾脏中未观察到该表型。我们 假设IRF-7在宿主内的两个独立位点介导独立的抗病毒功能。 在此提出的体内实验将提供一个广泛的，但集中的分析细胞和 IRF-7在宿主脾脏和腹腔中表达的分子重要性 γ疱疹病毒感染重要的是，这些研究的成功完成将提供深入了解 控制γ疱疹病毒感染，这将为受感染者提供潜在的治疗靶点 特别易受γ疱疹病毒的相关致癌作用的影响。