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

项目总结 伽马疱疹病毒在全球大多数人中建立终身感染，并 与癌症的发展有关，包括B细胞淋巴瘤。私密的 伽马疱疹病毒与B细胞分化的关系与 这些病毒的淋巴增殖能力。为了确保建立长期延迟， 记忆B细胞，伽马疱疹病毒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，即 以激活的B细胞快速分裂为特征，并由 诱导DNA断裂或突变DNA的酶。不足为奇的是，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 B细胞居中。这种由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的水平。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。我们已经确认了干扰素 调节因子-1(IRF-1)作为第一个特异性衰减的宿主因子 伽马疱疹病毒驱动的生发中心反应。这里提出的研究验证了这一假说 IRF-1是抑制伽马疱疹病毒驱动的扩张和 生发中心B细胞在终生感染过程中的转化。建议进行的研究 将定义IRF-1介导的信号变化，以减弱伽马疱疹病毒驱动的信号变化 生发中心反应的扩张及其对B细胞和T细胞的相对贡献 IRF-1对这一过程的作用。此外，拟议中的研究将开发一种新的动物模型 伽马疱疹病毒淋巴增生症。成功完成拟议的研究将 提供对IRF-1抑瘤机制的见解并产生新的动物 对传染病、免疫学和癌症领域有价值的模型。

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.