Interferon gamma inducible protein 16 and KSHV gene expression

描述（由申请人提供）：KSHV感染导致炎症相关的恶性肿瘤，如卡波西氏肉瘤（KS）和原发性积液b细胞淋巴瘤（PEL）。细胞因子和病毒基因产物在KSHV相关的恶性肿瘤中发挥作用。在体外，感染KSHV的内皮细胞分泌的细胞因子与在KSHV相关的KS和PEL病变中检测到的细胞因子相同。我们的总体假设是，KSHV利用和/或破坏宿主分子来调节其自身和宿主基因表达，以创造有利于建立和维持潜伏感染的环境。我们的总体目标是破译KSHV利用宿主分子进行感染的分子机制，这些知识将导致设计治疗策略，以消除KSHV潜伏期，炎症和相关的恶性肿瘤。KSHV利用IL-1 β的靶分子COX-2/PGE2在潜伏感染细胞中维持其潜伏基因的表达。成熟的IL-1 β是由一个传感器蛋白、适配器ASC蛋白和效应蛋白procaspase-1组成的炎性体的作用下形成的。在确定KSHV诱导IL-1 β的机制时，我们发现进入细胞核的KSHV DNA通过核驻留干扰素γ诱导蛋白16 （IFI16）诱导先天炎性小体反应。我们的研究也显示了人类PEL和KS病变中IFI16炎性体活化的证据。在KSHV潜伏感染的内皮细胞和PEL细胞中，只有ifi16炎性小体被激活。我们还发现，尽管有IFI16炎性小体诱导，但KSHV潜伏期仍然存在，并且在感染过程中，在感染细胞的细胞核以及潜伏感染的内皮细胞和PEL细胞的细胞核中，IFI16与KSHV基因组非常早地结合。我们假设KSHV利用IFI16进行潜在的基因表达。这一假设将通过本文提出的研究得到验证。这些研究具有重要意义，因为它们解决了我们关于KSHV如何利用宿主细胞核内先天反应来维持其基因表达的知识的基本空白，并探索了先天反应与病毒DNA表观遗传修饰之间的联系。这些研究将促进新疗法的发展，以消除KSHV潜伏感染和改善相关疾病。

DESCRIPTION (provided by applicant): KSHV infection results in inflammation associated malignancies such as Kaposi's sarcoma (KS) and primary effusion B-cell lymphoma (PEL). Cytokines and viral gene products play roles in KSHV associated malignancies. In vitro KSHV infected endothelial cells secrete cytokines that are identical to the cytokines detected in KSHV associated KS and PEL lesions. Our overall hypothesis is that KSHV utilizes and/or subverts host molecules to regulate its own and host gene expression to create an environment that is conducive for the establishment and maintenance of a latent infection. Our overall objectives are to decipher the molecular mechanism by which KSHV utilizes the host molecules for its infection with a rationale that such knowledge will lead into designing therapeutic strategies to eliminate KSHV latency, inflammation and the associated malignancies. KSHV utilizes COX-2/PGE2, the target molecules of IL-1 beta, to maintain its latent gene expression in latently infected cells. Mature IL-1 beta is formed due to the action of an inflammasome that is composed of a sensor protein, adaptor ASC protein and effector procaspase-1 protein. While defining the mechanism of IL-1 beta induction by KSHV, we made the novel discovery that KSHV DNA entering the nucleus induces the innate inflammasome response via the nuclear resident interferon gamma-inducible protein 16 (IFI16). Our studies also showed evidence of IFI16 inflammasome activation in human PEL and KS lesions. Only the IFI16-inflammasome is activated in KSHV latently infected endothelial and PEL cells. We also discovered that KSHV latency persists despite the IFI16-inflammasome induction and IFI16 associates with the KSHV genome very early during infection in the nucleus of infected cells and in the nuclei of latently infected endothelial and PEL cells. We hypothesize that KSHV utilizes IFI16 for its latent gene expression. This hypothesis will be tested by studies proposed here. These studies are significant as they address a fundamental gap in our knowledge regarding how KSHV utilizes a host cell innate response in the nucleus to maintain its gene expression and explore the link between innate response and epigenetic modifications of viral DNA. These studies will facilitate the development of novel therapies to eliminate KSHV latent infection and ameliorate the associated diseases.