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: 10592356
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592356
• 关键词: Acetylation; Africa South of the Sahara; B-Cell Lymphomas; B-Lymphocytes; BRCA1 gene; Binding; Binding Proteins; Biology; Blood Vessels; CASP1 gene; Cell Nucleus; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Country; Cytoplasm; 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; IL18 gene; Immune; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type II; Interferon alpha; Interferon-beta; Interleukin-1 beta; 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; Proliferating; Proteins; Role; Sexually Transmitted Agents; Signal Transduction; Stimulator of Interferon Genes; TNF gene; Testing; Therapeutic; Time; Transcription Repressor; Transferase; Vascular Endothelial Cell; Viral Proteins; cytokine; effusion; knock-down; macroH2A histone; novel strategies; p300/CBP-Associated Factor; pathogen; primary effusion lymphoma; promoter; response; sensor; viral DNA; Acetylation; Africa South of the Sahara; B-Cell Lymphomas; B-Lymphocytes; BRCA1 gene; Binding; Binding Proteins; Biology; Blood Vessels; CASP1 gene; Cell Nucleus; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Country; Cytoplasm; 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; IL18 gene; Immune; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type II; Interferon alpha; Interferon-beta; Interleukin-1 beta; 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; Proliferating; Proteins; Role; Sexually Transmitted Agents; Signal Transduction; Stimulator of Interferon Genes; TNF gene; Testing; Therapeutic; Time; Transcription Repressor; Transferase; Vascular Endothelial Cell; Viral Proteins; 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的防御机制来识别，反应和控制 他们每天遇到的许多病原体和有害物质。先天免疫反应是 以非特异性方式做出反应和辩护的第一批防御线之一。 KSHV是性的 在美国和西方国家传播特工，并在撒哈拉以南非洲的生命早期感染。在 免疫抑制的个体，KSHV在病因上与炎症相关的恶性肿瘤相关 例如Kaposi的肉瘤（KS），主要积液B细胞淋巴瘤（PEL）和多中心Castleman's 疾病（MCD）。诸如IL-1β，TNF-α，IFN-γ和IL-6以及病毒基因产物等细胞因子被提出 驱动KS，PEL和MCD的发展和进展。内皮细胞的KSHV感染影响 与KS/PEL/MCD病变的微环境相似的炎性细胞因子和生长因子。 我们假设KSHV不断激活先天PRR可能是慢性的原因之一 在KS，PEL和MCD病变中看到的炎症。因此，我们的总体目标是定义先天免疫 对KSHV的反应并确定其在KSHV生物学中的作用。 我们已经表明，在人类皮肤的从头kshv感染期间引起的细胞因子曲线 微血管内皮细胞与KS/PEL/MCD病变微环境和促值相同 炎症性IL-1β和IL-18细胞因子在上清液中分泌。 IL-1β和IL-18 pro形式经历 通过激活的caspase-1处理。 caspase-1，合成为procaspase-1，被自动催化 由传感器蛋白传感器形成的分子平台“炎症体”危险信号，适配器 分子ASC和procaspase-1。先天的反应是否识别并响应外染色体 核中的DS圆形KSHV基因组（和其他DNA病毒）尚不清楚。我们的学习是第一次 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的延迟维持中起作用。基于这些研究，我们扩展了原始 假设和假设是“ IFI16与核中不同蛋白的复杂性介导了不同 包括偶发DNA和KSHV的先天灵敏度在内的功能都利用/颠覆IFI16及其相关的功能 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 已经提出了两个主要的重点和相互联系的特定目标。这些研究很重要，因为 阐明IFI16及其相关蛋白在KSHV潜伏期中的作用将允许更深入 了解其发病机理，这将有助于控制KSHV的治疗性操纵 感染，感染和相关的恶性肿瘤。