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Cell Intrinsic Immune Control of KSHV

KSHV 的细胞内在免疫控制

基本信息

批准号：
10063473
负责人：
John Karijolich
金额：
$ 42.46万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063473
关键词：
Acquired Immunodeficiency Syndrome Antiviral Agents B-Lymphocytes Binding Biogenesis Cancer Etiology Cells Chemical Structure Cyclic GMP DNA Data Defect Defective Viruses Development Disease Disease Progression Enzymes Etiology Family Genetic Transcription Germ Lines HIV Herpesviridae Infections Host Defense Human Herpesvirus 8 Immune Immune response Immune system Immunocompromised Host Immunosuppression Individual Infection Interferons Kaposi Sarcoma Knowledge Ligands Link Lymphoproliferative Disorders Lytic Lytic Phase Malignant Neoplasms Maps Mediating Modification Molecular Molecular Structure Multicentric Angiofollicular Lymphoid Hyperplasia Nucleic Acids Oncogenic Organism Outcome Pathway interactions Patients Pattern Pattern recognition receptor Plasma Cells Process Production Proteins RNA RNA Binding RNA Helicase RNA Viruses Regulation Ribonucleases Role Shapes Signal Transduction Structure TLR9 gene Testing Untranslated RNA Vaccine Therapy Variant Virus anti-cancer base chemical property cytosolic receptor endonuclease experimental study gammaherpesvirus genetic information in vivo pathogen primary effusion lymphoma receptor receptor binding response sensor transcriptome transcriptomics viral RNA

项目摘要

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma-herpesvirus and an AIDS-associated pathogen. KSHV is associated with Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease. KSHV-associated disease occurs more commonly in immunocompromised individuals, indicating an intricate relationship between disease progression and the host immune system. It is well established that cell intrinsic immune sensors, and in particular the DNA sensors Toll-like receptor 9 (TLR9) and cyclic GMP-AMP synthase (cGAS), sense KSHV infection. However, it is less clear whether RNA sensors, such as the RIG-I like receptors RIG-I and MDA5, participate in host defense against KSHV. Data within this proposal demonstrate that RIG-I and MDA5 impose a significant restriction on KSHV lytic reactivation in PEL. Using high- throughput transcriptomics we have defined the RNAs that are recognized by RIG-I and MDA5 during KSHV lytic infection in PEL, and this proposal builds upon our observations. These studies will enable us to (Aim 1) determine the contribution of RLR-associated RNAs to KSHV restriction, (Aim 2) determine how KSHV-encoded proteins impact RIG-I and MDA5 sensing, and (Aim 3) identify the precise mechanism of MDA5 activation during KSHV infection. Completion of these studies will provide fundamental knowledge regarding how the cell intrinsic immune response is activated during KSHV infection.

卡波西肉瘤相关疱疹病毒（KSHV）是一种致癌的γ-疱疹病毒和艾滋病相关病原体。KSHV与卡波西肉瘤（KS）、原发性渗出性淋巴瘤（PEL）和多中心Castleman病有关。KSHV相关疾病更常见于免疫功能低下的个体，表明疾病进展与宿主免疫系统之间存在复杂的关系。已经充分确定，细胞内在免疫传感器，特别是DNA传感器Toll样受体9（TLR 9）和环GMP-AMP合酶（cGAS）感测KSHV感染。然而，目前尚不清楚RNA传感器，如RIG-I样受体RIG-I和MDA 5，是否参与宿主对KSHV的防御。本提案中的数据表明，RIG-I和MDA 5对PEL中的KSHV裂解再活化施加了显著限制。使用高通量转录组学，我们已经定义了在PEL中KSHV裂解感染期间被RIG-I和MDA 5识别的RNA，并且该提议建立在我们的观察基础上。这些研究将使我们能够（目的1）确定RLR相关RNA对KSHV限制的贡献，（目的2）确定KSHV编码的蛋白质如何影响RIG-I和MDA 5传感，以及（目的3）确定KSHV感染期间MDA 5激活的精确机制。这些研究的完成将提供关于KSHV感染期间细胞内在免疫应答如何被激活的基础知识。