Modulation of Herpes Simplex Virus Pathogenesis by Leucine Rich Repeat Kinase 2

富含亮氨酸重复激酶 2 对单纯疱疹病毒发病机制的调节

基本信息

批准号：
10427420
负责人：
Andrew Hoover Karaba
金额：
$ 19.87万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-11 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427420
关键词：
Adult Alleles Bacterial Infections Binding Biometry Blindness Cell Death Cell Line Cells Cornea Crohn&apos s disease Cutaneous Data Development Plans Disease Disease model Encephalitis Etiology Eye Family Flow Cytometry General Population Genes Herpes encephalitis Herpesviridae Herpesvirus 1 High Prevalence Human Immune Immune response Immunocompromised Host Immunohistochemistry Immunologics Immunology Infection Infection Control Inflammasome Inflammation Inflammatory Innate Immune Response Innate Immune System Integration Host Factors Interleukin-1 Interleukin-18 Intervention Keratitis Knockout Mice Knowledge LRRK2 gene Lead Learning Leprosy Lesion Life Malignant Neoplasms Measurable Measures Mediating Mentorship Modeling Morbidity - disease rate Multiprotein Complexes Mus Mutagenesis Mutation Natural Immunity Neuraxis Organ Outcome Parkinson Disease Pathogenesis Pathogenicity Pathology Pathway interactions Population Production Regulation Research Personnel Research Training Role Severities Signal Pathway Signal Transduction Simplexvirus Skin System Testing Tissues Training Transfection Transgenic Mice Tumor-infiltrating immune cells United States Vaccines Viral Viral Encephalitis Viral Pathogenesis Virulence Virus Virus Diseases Virus Replication career career development cell type chemokine cytokine immune activation in vivo macrophage marenostrin mortality mouse LRRK2 protein mouse model mutant neurotropic neurotropic virus novel novel therapeutics pathogen programs research and development response skills stable cell line

项目摘要

PROJECT SUMMARY In the United States, herpes simplex virus type 1 (HSV-1) infects more than half the adult population and is the leading cause of viral encephalitis and infectious blindness. Yet, the host factors contributing to the most severe manifestations of HSV-1 remain unclear. Inflammasomes, a recently discovered antiviral innate immune defense, and the production of two inflammasome cytokines (interleukin (IL)-1and IL-18) are critical in HSV-1 control and pathogenesis. However, how inflammasomes are regulated during HSV-1 infection is poorly understood. Recently, leucine-rich repeat kinase 2 (LRRK2) has emerged as a possible regulator of inflammasome signaling. LRRK2 has been studied extensively because specific alleles are associated with Parkinson’s disease, Crohn’s disease, cancer, and leprosy. Despite the disease associations, the precise function of LRRK2 and how it mediates disease are unknown. Evidence for a role in the immune response include that LRRK2 is highly expressed on immune cells, is upregulated in response to infection, and was recently shown to modulate the NLRC4 inflammasome in response to bacterial infection. We recently demonstrated that NLRP3 is critical in inflammasome activation by HSV-1, and our preliminary data indicate that LRRK2 enhances NLRP3 signaling. We found that the common LRRK2 mutation G2019S enhances HSV- 1 pathology in mice without altering viral replication. These results point to a novel role for LRRK2 in inflammasome signaling and HSV-1 pathogenesis. We hypothesize that LRRK2 modulates inflammasome signaling in response to HSV-1 infection and that the G2019S mutation further enhances inflammasome activation in vivo, leading to more severe eye, skin, and central nervous system (CNS) pathology after HSV-1 infection. LRRK2 has not been studied in human viral infection, and these represent the first studies to define its role in the pathogenesis of a common neurotropic human viral infection. In Aim 1, we will identify how LRRK2 associates with NLRP3, the critical inflammasome adapter in HSV-1 infection, and how mutations in LRRK2 alter inflammasome signaling in the context of HSV-1 infection. We will accomplish this by using targeted mutagenesis in a transfection model of inflammasome signaling and by studying inflammasome activation after HSV-1 infection of cell lines stably expressing LRRK2 mutants. For Aim 2, we will determine how LRRK2 alters the inflammasome response to HSV-1 using LRRK2 transgenic mice and mice with inflammasome gene disruptions. Additionally, the PI will gain critical skills and expertise necessary to study the innate immune response to HSV-1 and other herpesviruses. These learning objectives will be accomplished through formal coursework, scientific programing, and direct mentorship by experts in viral and murine immunology, herpesvirology, and biostatistics. The proposed career development plan and research aims will provide a pathway to a career as an independent investigator studying the interactions between herpesviruses and the innate immune system.

项目概要在美国，1 型单纯疱疹病毒 (HSV-1) 感染了一半以上的成年人口，是然而，宿主因素是导致病毒性脑炎和感染性失明的主要原因。 HSV-1 炎症小体（一种最近发现的天然抗病毒药物）的严重表现尚不清楚。免疫防御和两种炎性细胞因子（白细胞介素 (IL)-1和 IL-18）的产生至关重要然而，HSV-1 感染期间炎症小体的调节方式尚不清楚。最近，富含亮氨酸重复激酶 2 (LRRK2) 已成为一种可能的调节因子。研究 LRRK2 炎症小体信号传导主要是因为特定等位基因与相关。帕金森氏病、克罗恩氏病、癌症和麻风病尽管存在疾病关联，但确切地说。 LRRK2 的功能以及它如何介导疾病尚不清楚。包括 LRRK2 在免疫细胞上高表达，响应感染而上调，并且最近，我们发现它可以调节 NLRC4 炎症小体来应对细菌感染。 NLRP3 在 HSV-1 炎症小体激活中至关重要，我们的初步数据表明 LRRK2 增强 NLRP3 信号传导，我们发现常见的 LRRK2 突变 G2019S 增强 HSV- 1 在不改变病毒复制的情况下，小鼠的病理学结果表明 LRRK2 在小鼠中具有新的作用。我们追踪 LRRK2 调节炎症小体。 HSV-1 感染的信号传导以及 G2019S 突变进一步增强炎症小体 HSV-1 后体内激活，导致更严重的眼睛、皮肤和中枢神经系统 (CNS) 病理 LRRK2 尚未在人类病毒感染中进行过研究，这些代表了首次定义的研究。在目标 1 中，我们将确定其在常见的嗜神经性人类病毒感染的发病机制中的作用。 LRRK2 与 NLRP3 相关，NLRP3 是 HSV-1 感染中的关键炎症小体接头，以及突变如何 LRRK2 在 HSV-1 感染的情况下改变炎症小体信号传导，我们将通过使用来实现这一点。通过研究炎症小体，在炎症小体信号转染模型中进行靶向突变 HSV-1 感染稳定表达 LRRK2 突变体的细胞系后的激活对于目标 2，我们将确定。 LRRK2 如何使用 LRRK2 转基因小鼠和小鼠来改变对 HSV-1 的炎症小体反应此外，PI 将获得研究炎症体基因破坏所需的关键技能和专业知识。对 HSV-1 和其他疱疹病毒的先天免疫反应将实现这些学习目标。通过正式课程、科学规划以及病毒和鼠类专家的直接指导拟议的职业发展计划和研究目标将是免疫学、疱疹病毒学和生物统计学。为研究疱疹病毒之间相互作用的独立研究者提供一条职业道路和先天免疫系统。