Interferon gamma inducible protein 16 and KSHV gene expression

干扰素γ诱导蛋白16和KSHV基因表达

• 批准号: 8769399
• 负责人: Bala Chandran
• 金额: $ 23.18万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-11 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769399
• 关键词: Adaptor Signaling Protein; Address; Antibodies; Apoptosis; Apoptotic; Autophagocytosis; B-Cell Lymphomas; B-Lymphocytes; Binding; Caspase-1; Cell Nucleus; Cells; ChIP-on-chip; Cytoplasm; DNA; Dermal; Development; Dinoprostone; Disease; Endothelial Cells; Environment; Epigenetic Process; Epithelial Cells; Gene Expression; Genes; Genome; Herpesviridae; Human; Human Herpesvirus 8; In Vitro; Infection; Inflammation; Inflammatory; Interferon Type II; Interleukin-1; Interleukin-18; Kaposi Sarcoma; Knowledge; Lead; Lesion; Link; Lytic; Lytic Phase; Maintenance; Malignant Neoplasms; Methods; Modification; Molecular; Nuclear; PTGS2 gene; Pathogenesis; Play; Process; Promoter Regions; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Role; Small Interfering RNA; Subfamily lentivirinae; Testing; Therapeutic; Time; Vascular Endothelial Growth Factors; Viral Genes; Viral Proteins; Virus; cohesin; cytokine; design; effusion; in vitro Model; in vivo; latent gene expression; latent infection; lytic gene expression; next generation sequencing; novel; procaspase-1; public health relevance; response; sensor; small hairpin RNA; viral DNA

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.

描述（由申请方提供）：KSHV感染导致炎症相关恶性肿瘤，如卡波西肉瘤（KS）和原发性渗出性B细胞淋巴瘤（PEL）。细胞因子和病毒基因产物在KSHV相关恶性肿瘤中发挥作用。体外KSHV感染的内皮细胞分泌的细胞因子与KSHV相关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/或颠覆宿主分子来调节自身和宿主基因表达，以创造一个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的靶分子考克斯-2/PGE 2来维持其在潜伏感染细胞中的潜伏基因表达。成熟的IL-1 β是由于炎性小体的作用而形成的，炎性小体由传感器蛋白、衔接子ASC蛋白和效应子半胱氨酸天冬氨酸蛋白酶原-1蛋白组成。在确定KSHV诱导IL-1 β的机制时，我们发现KSHV DNA进入细胞核通过细胞核内的干扰素γ诱导蛋白16（IFI 16）诱导先天性炎性小体反应。我们的研究还显示了在人PEL和KS病变中IFI 16炎性小体活化的证据。只有IFI 16-炎性体在KSHV潜伏感染的内皮细胞和PEL细胞中被激活。我们还发现，尽管IFI 16-炎性小体诱导，KSHV潜伏期仍然存在，并且IFI 16在感染细胞的细胞核和潜伏感染的内皮细胞和PEL细胞的细胞核中感染期间非常早地与KSHV基因组相关联。我们假设KSHV利用IFI 16进行其潜伏基因表达。这一假设将通过本文提出的研究进行检验。这些研究具有重要意义，因为它们解决了我们关于KSHV如何利用细胞核中的宿主细胞先天反应来维持其基因表达的知识中的根本空白，并探索了先天反应与病毒DNA的表观遗传修饰之间的联系。这些研究将有助于开发新的治疗方法，以消除KSHV潜伏感染和改善相关疾病。