KSHV interactions with host inflammasome components

KSHV 与宿主炎症小体成分的相互作用

• 批准号: 9532411
• 负责人: Bala Chandran
• 金额: $ 25.72万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-07 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9532411
• 关键词: Acetylation; Apoptosis; Area; B-Cell Lymphomas; B-Lymphocytes; Biological Assay; Bromodeoxyuridine; CASP1 gene; Cell Line; Cell Nucleus; Cells; ChIP-on-chip; Chronic; Complex; Cytokine Gene; Cytoplasm; D Cells; DNA; DNA Binding; DNA Damage; DNA Viruses; Defense Mechanisms; Dermal; Disease; Elements; Endothelial Cells; Epstein-Barr Virus latency; Etiology; Genome; Goals; HIV-1; Herpesviridae Infections; Herpesvirus 1; Histone H2B; Human; Human Herpesvirus 4; Human Herpesvirus 8; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type II; Interleukin-1 beta; Interleukin-18; Kaposi Sarcoma; Knowledge; Label; Lead; Lesion; Ligation; Link; Lytic; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Microscopy; Modification; Molecular; Nuclear; Oral; Pathogenesis; Pathway interactions; Patients; Phase; Primary Infection; Proteins; Proteolytic Processing; Regulator Genes; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Site; Testing; Therapeutic; Time; Viral Proteins; cytokine; design; effusion; fast protein liquid chromatography; genome editing; innovation; knock-down; new technology; next generation sequencing; novel; pathogen; primary effusion lymphoma; promoter; public health relevance; response; sensor; transcriptome sequencing

DESCRIPTION: KSHV is etiologically associated with chronic inflammation associated Kaposi's sarcoma (KS) and primary effusion B-cell lymphoma (PEL) in oral and other body sites that occur in HIV-1 infected patients. The inflammatory response is one of the key elements of KSHV pathogenesis. KS lesions are characterized by inflammatory cells and cytokines. The KS lesion endothelial cells and B-cell lines from PEL carry multiple copies of the KSHV genome in a latent state. Our long term goals are to elucidate KSHV's interactions with the host innate response during primary infection and latency, the pathways of cytokine induction and to define their role in KSHV pathogenesis. Our rationale is that such detailed knowledge is crucial for designing therapeutic strategies to control KSHV infection, inflammation and the associated malignancies. KSHV infected cells secrete multi-functional IL-1ß and IL-18 cytokines into the supernatants. IL-1ß and IL-18 are synthesized as inactive proIL-1ß and proIL-18 and then undergo processing by activated caspase-1. However, caspase-1 itself is synthesized as a procaspase-1 and undergoes activation leading into an auto- proteolytic cleavage. Procaspase-1 activation is mediated by a molecular platform called an "inflammasome" that is formed by homotypic interactions of a sensor protein recognizing the danger trigger, an adaptor ASC molecule, and procaspase-1. Our studies have demonstrated that the pathogen sensing functions of the inflammasome also extends into the nucleus. During de novo KSHV infection of human microvascular dermal endothelial (HMVEC-d) cells, gamma-interferon-inducible protein (IFI16) is colocalized with the KSHV genome in the infected endothelial cell nucleus, and interacted with ASC and procaspase-1 to form an inflammasome complex. IFI16 also colocalized with the KSHV genome in the nuclei of latently infected endothelial and PEL cells, and only the IFI16 dependent inflammasome is constitutively activated in KSHV latently infected cells. Human KS and PEL lesions showed evidence of IFI16-ASC inflammasome activation. Constitutive induction of the IFI16-inflammasome was also observed in γ1-EBV latency I, II and III cells. Together with the ability of KSHV and EBV latency in the presence of the IFI16-inflammasome and association of IFI16 with KSHV and EBV genome in the latently infected cells, we hypothesize that "IFI16 is involved in the innate sensing of foreign episomal DNA in the nucleus and KSHV utilizes IFI16 for its latency". This hypothesis will be tested by three innovative and interlinked specific aims. These studies are significant since such elucidation wil lead into designing therapeutic strategies to control KSHV induced inflammation and the associated malignancies. These will also profoundly enhance the current concepts of innate sensing in the nucleus and will lead into new technologies and treatments that will benefit not only the KSHV area of research but also other fields.

描述：KSHV在病因学上与慢性炎症相关的卡波西肉瘤（KS）和发生在HIV-1感染患者口腔和其他身体部位的原发性积液b细胞淋巴瘤（PEL）相关。炎症反应是KSHV发病机制的关键因素之一。KS病变以炎症细胞和细胞因子为特征。来自PEL的KS病变内皮细胞和b细胞系在潜伏状态下携带多个KSHV基因组拷贝。我们的长期目标是阐明KSHV在原发性感染和潜伏期间与宿主先天反应的相互作用，细胞因子诱导的途径，并确定它们在KSHV发病机制中的作用。我们的基本原理是，这些详细的知识对于设计控制KSHV感染、炎症和相关恶性肿瘤的治疗策略至关重要。感染KSHV的细胞分泌多种功能的IL-1ß和IL-18细胞因子进入上清液。IL-1ß和IL-18合成为失活的proIL-1ß和proIL-18，然后通过活化的caspase-1进行加工。然而，caspase-1本身是作为procaspase-1合成的，并经过激活导致自蛋白水解裂解。Procaspase-1的激活是由一个称为“炎性体”的分子平台介导的，该平台是由识别危险触发的传感器蛋白、适配器ASC分子和Procaspase-1的同型相互作用形成的。我们的研究表明，炎症小体的病原体感应功能也延伸到细胞核。在人微血管真皮内皮细胞（HMVEC-d）新生KSHV感染过程中，γ -干扰素诱导蛋白（IFI16）在被感染的内皮细胞核中与KSHV基因组共定位，并与ASC和procaspase-1相互作用形成炎性小体复合物。在潜伏感染的内皮细胞和PEL细胞的细胞核中，IFI16也与KSHV基因组共定位，并且在KSHV潜伏感染的细胞中，只有IFI16依赖性炎症小体被组成性激活。人类KS和PEL病变显示IFI16-ASC炎性体活化的证据。在γ - 1- ebv潜伏期I、II和III细胞中也观察到ifi16炎性体的组成性诱导。结合IFI16炎性体存在时KSHV和EBV潜伏期的能力，以及IFI16与潜伏感染细胞中KSHV和EBV基因组的关联，我们假设“IFI16参与细胞核内外源外体DNA的先天感知，KSHV利用IFI16进行潜伏期”。这一假设将通过三个创新和相互关联的具体目标来检验。这些研究是重要的，因为这些阐明将导致设计治疗策略来控制KSHV诱导的炎症和相关的恶性肿瘤。这些也将深刻地增强当前的核先天感知概念，并将导致新的技术和治疗，这不仅有利于KSHV研究领域，也有利于其他领域。