KSHV interactions with host nuclear innate response components

KSHV 与宿主核先天反应成分的相互作用

• 批准号: 10375451
• 负责人: Bala Chandran
• 金额: $ 35.51万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375451
• 关键词: Acetylation; Africa South of the Sahara; B-Cell Lymphomas; B-Lymphocytes; BRCA1 gene; Binding; Binding Proteins; Biology; CASP1 gene; Cell Nucleus; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Country; DNA; DNA Viruses; Defense Mechanisms; Dermal; Development; Endothelial Cells; Epigenetic Process; Epstein-Barr Virus latency; Etiology; Follow-Up Studies; Gene Expression; Generations; Genes; Genetic Transcription; Genome; Goals; Grant; Growth Factor; Herpesviridae; Herpesvirus 1; Histone H2B; Histones; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type II; Interferon-alpha; Interferon-beta; Interferons; Interleukin-1 beta; Interleukin-18; Interleukin-6; Investigation; Kaposi Sarcoma; Knock-out; Knowledge; Label; Lead; Lesion; Life; Lytic; Lytic Phase; Maintenance; Malignant Neoplasms; Mediating; Methylation; Modification; Molecular; Multicentric Angiofollicular Lymphoid Hyperplasia; Nuclear; Nuclear Protein; Nuclear Translocation; Organism; Pathogenesis; Pathway interactions; Pattern recognition receptor; Play; Production; Proteins; Role; Sexually Transmitted Agents; Signal Transduction; Stimulator of Interferon Genes; TNF gene; Testing; Therapeutic; Time; Transcription Repressor; Transferase; Viral Genome; Viral Proteins; base; cytokine; effusion; knock-down; macroH2A histone; novel strategies; p300/CBP-Associated Factor; pathogen; primary effusion lymphoma; promoter; response; sensor; viral DNA

Eukaryotic organisms have an array of defense mechanisms to recognize, respond and control the numerous pathogens and harmful substances that they encounter every day. The Innate immune response is one of the first lines of defense to respond and defend in a non-specific manner. KSHV is a sexually transmitted agent in the USA and Western countries, and infects early during life in sub-Saharan Africa. In immune-suppressed individuals, KSHV is etiologically associated with inflammation associated malignancies such as Kaposi’s sarcoma (KS), primary effusion B-cell lymphoma (PEL), and Multicentric Castleman’s disease (MCD). Cytokines such as IL-1β, TNF-α, IFN-γ and IL-6 as well as viral gene products are proposed to drive KS, PEL and MCD development and progression. KSHV infection of endothelial cells induces inflammatory cytokines and growth factors which are similar to the microenvironments of KS/PEL/MCD lesions. We hypothesize that constant activation of innate PRRs by KSHV could be one of the reasons for the chronic inflammation seen in KS, PEL and MCD lesions. Hence, our overall goals are to define the innate immune response against KSHV and to determine its role in KSHV’s biology. We have shown that the cytokine profiles elicited during de novo KSHV infection of human dermal microvascular endothelial cells are identical to the KS/PEL/MCD lesion microenvironments and pro- inflammatory IL-1β and IL-18 cytokines are secreted in the supernatants. IL-1β and IL-18 pro-forms undergo processing by activated caspase-1. Caspase-1, synthesized as procaspase-1, is auto-catalytically cleaved by the molecular platform “inflammasome” that is formed by a sensor protein sensing the danger signal, adaptor molecule ASC and procaspase-1. Whether innate responses recognize and respond to the extra-chromosomal ds-circular KSHV genome (and other DNA viruses) in the nuclei were not known. Our studies for the first time demonstrated that IFI16, a highly conserved nuclear protein involved in transcription by unknown mechanism, is an innate nuclear sensor of KSHV, EBV and HSV-1 genomes. Follow up studies have revealed that IFI16 plays a role in latency maintenance of KSHV. Based on these studies we have extended our original hypothesis and hypothesize that "IFI16 is in complex with different proteins in the nucleus to mediate different functions including innate sensing of episomal DNA and KSHV utilizes/subverts IFI16 and its associated proteins for its latency". Our exciting preliminary studies supports this hypothesis. To test this hypothesis, we have formulated two major focused and interlinked specific aims. These studies are significant since elucidating the role of IFI16 and its associated proteins in the nucleus in KSHV’s latency will allow a deeper understanding of its pathogenesis which will facilitate therapeutic manipulation of this pathway to control KSHV infection, inflammation and the associated malignancies.

真核生物具有一系列防御机制来识别、响应和控制 他们每天都会遇到许多病原体和有害物质。先天免疫反应是 以非特定方式做出反应和防御的第一道防线之一。 KSHV 是一种性 在美国和西方国家传播，并在撒哈拉以南非洲的生命早期感染。在 在免疫抑制个体中，KSHV 在病因学上与炎症相关的恶性肿瘤有关 例如卡波西肉瘤 (KS)、原发性渗出性 B 细胞淋巴瘤 (PEL) 和多中心 Castleman 淋巴瘤 疾病（MCD）。细胞因子如 IL-1β、TNF-α、IFN-γ 和 IL-6 以及病毒基因产物被提议 推动 KS、PEL 和 MCD 的发展和进步。 KSHV感染内皮细胞诱导 炎症细胞因子和生长因子，与 KS/PEL/MCD 病变的微环境相似。 我们假设 KSHV 持续激活先天 PRR 可能是慢性疾病的原因之一。 KS、PEL 和 MCD 病变中可见炎症。因此，我们的总体目标是定义先天免疫 针对 KSHV 的反应并确定其在 KSHV 生物学中的作用。 我们已经证明，KSHV 从头感染人类真皮时会引发细胞因子谱。 微血管内皮细胞与 KS/PEL/MCD 病变微环境相同，并且亲 上清液中分泌炎症性IL-1β和IL-18细胞因子。 IL-1β 和 IL-18 前体经历 由激活的 caspase-1 进行处理。 Caspase-1，合成为 procaspase-1，被自动催化裂解 由感知危险信号的传感器蛋白、适配器形成的分子平台“炎性体” 分子 ASC 和 procaspase-1。先天反应是否识别并响应染色体外 细胞核中的双链环状 KSHV 基因组（和其他 DNA 病毒）尚不清楚。我们第一次学习 证明 IFI16 是一种高度保守的核蛋白，通过未知机制参与转录， 是 KSHV、EBV 和 HSV-1 基因组的先天核传感器。后续研究表明，IFI16 在 KSHV 的潜伏期维持中发挥作用。基于这些研究，我们扩展了我们原来的 假设“IFI16 与细胞核中的不同蛋白质形成复合物，介导不同的 功能包括附加型 DNA 的先天感知和 KSHV 利用/颠覆 IFI16 及其相关 蛋白质的潜伏期”。我们令人兴奋的初步研究支持了这一假设。为了检验这一假设，我们 制定了两大重点突出且相互关联的具体目标。这些研究意义重大，因为 阐明 IFI16 及其在细胞核中相关蛋白在 KSHV 潜伏期中的作用将有助于更深入地了解 KSHV 的潜伏期。 了解其发病机制将有助于对该途径进行治疗操作以控制 KSHV 感染、炎症和相关的恶性肿瘤。