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; 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在病理学上与慢性炎症相关的Kaposi的肉瘤（KS）和原发性B细胞淋巴瘤（PEL）在受HIV-1感染患者中发生的口服和其他身体部位相关。炎症反应是KSHV发病机理的关键要素之一。 KS病变的特征是炎症细胞和细胞因子。来自PEL的KS病变内皮细胞和B细胞系在潜在状态下带有KSHV基因组的多个副本。我们的长期目标是阐明KSHV在原发性感染和潜伏期期间与宿主先天反应的相互作用，细胞因子诱导的途径，并定义它们在KSHV发病机理中的作用。我们的理由是，这种详细的知识对于设计理论策略以控制KSHV感染，感染和相关的恶性肿瘤至关重要。 KSHV感染的细胞将多功能的IL-1ß和IL-18细胞因子秘密地秘密地进入上清液。 IL-1ß和IL-18合成为无活性的proil-1ß和proil-18，然后通过激活的caspase-1进行处理。但是，caspase-1本身被合成为procaspase-1，并经历导致自身蛋白溶解裂解的激活。 procaspase-1激活是由一个称为“炎症体”的分子平台介导的，该平台是由传感器蛋白识别危险触发的传感器蛋白的同型相互作用而形成的，该危险触发器，一个衔接子ASC分子和procaspase-1。我们的研究表明，炎性体的病原体感应功能也延伸到核。在人类微血管真皮内皮（HMVEC-D）细胞中，在从头KSHV感染过程中，γ-与Interferon诱导的蛋白（IFI16）与感染的内皮细胞核中的KSHV基因组共定位，并与ASC和Procaspase-1相互作用，形成炎症酶。 IFI16也与潜在感染的内皮细胞和pEL细胞的核中的KSHV基因组共定位，并且只有IFI16依赖性炎症体在kSHV潜在地受感染的细胞中持续激活。人类KS和PEL病变显示了IFI16-ASC炎性体激活的证据。在γ1-EBV潜伏期I，II和III细胞中也观察到了IFI16-炎症组的组成型诱导。在IFI16-炎症体和IFI16与KSHV和EBV基因组之间存在IFI16-炎症体和EBV基因组中的能力，我们假设“ IFI16与Nucleus and Kshv中外来偶发性DNA的先天敏感性有关。该假设将通过三个创新和相互联系的特定目的来检验。这些研究很重要，因为这种阐明将导致设计理论策略，以控制KSHV诱导的注射和相关的恶性肿瘤。这些还将深刻地增强当前在细胞核中先天感应的概念，并将导致新技术和处理不仅有益于KSHV研究领域，而且将使其他领域受益。