Cell Intrinsic Immune Control of KSHV

KSHV 的细胞内在免疫控制

基本信息

批准号：
10299621
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/10299621
关键词：
Acquired Immunodeficiency Syndrome B-Lymphocytes Binding Biogenesis Cancer Etiology Cells Chemicals Cyclic GMP DNA Data Defect Defective Viruses 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 TLR9 gene Testing Untranslated RNA Vaccine Therapy Variant Virus anti-cancer antiviral drug development 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) 是一种致癌性 γ-疱疹病毒，是一种与艾滋病相关的病原体，与卡波西肉瘤 (KS)、原发性渗出性淋巴瘤 (PEL) 和多中心性 KSHV 相关疾病有关。在免疫功能低下的个体中，表明疾病进展与宿主免疫系统之间存在复杂的关系。众所周知，细胞内在免疫传感器，特别是免疫传感器。 DNA 传感器 Toll 样受体 9 (TLR9) 和环 GMP-AMP 合酶 (cGAS) 感知 KSHV 感染，但尚不清楚 RIG-I 样受体 RIG-I 和 MDA5 等 RNA 传感器是否参与其中。该提案中的数据表明，RIG-I 和 MDA5 对 PEL 中的 KSHV 裂解再激活有显着的限制，我们使用高通量转录组学定义了PEL 中 KSHV 裂解感染期间 RIG-I 和 MDA5 识别的 RNA，该提议建立在我们的观察基础上，这些研究将使我们能够（目标 1）确定 RLR 相关 RNA 对 KSHV 限制的贡献。）确定 KSHV 编码的蛋白质如何影响 RIG-I 和 MDA5 传感，并（目标 3）确定 KSHV 感染期间 MDA5 激活的精确机制。将提供有关 KSHV 感染期间如何激活细胞内在免疫反应的基础知识。