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.

项目摘要在美国，单纯疱疹病毒1型（HSV-1）感染超过一半的成年人群，是病毒脑炎和传染性失明的主要原因。然而，宿主因素最大程度最大 HSV-1的严重表现尚不清楚。炎症，最近发现的抗病毒先天免疫防御和两种炎性细胞因子（白介素（IL）-1和IL-18）的产生至关重要在HSV-1控制和发病机理中。但是，在HSV-1感染期间如何调节炎症体是理解不佳。最近，富含亮氨酸的重复激酶2（LRRK2）已成为可能的调节剂炎症体信号传导。 LRRK2已被广泛研究，因为特定等位基因与帕金森氏病，克罗恩病，癌症和麻风病。尽管有疾病的关联，但精度 LRRK2及其介导疾病的功能尚不清楚。在免疫响应中发挥作用的证据包括lrrk2在免疫细胞上高度表达，以响应感染而更新，并且最近显示，可以根据细菌感染调节NLRC4炎症体。我们最近证明NLRP3在HSV-1的炎性体激活中至关重要，我们的初步数据表明该LRRK2增强了NLRP3信号传导。我们发现，常见的LRRK2突变G2019S增强了HSV- 1小鼠的病理，而不会改变病毒复制。这些结果表明LRRK2在炎性体信号传导和HSV-1发病机理。我们假设LRRK2调节炎症体响应HSV-1感染的信号传导，而G2019S突变进一步增强了炎症体在体内激活，导致HSV-1后更严重的眼睛，皮肤和中枢神经系统（CNS）病理感染。 LRRK2尚未在人类病毒感染中研究，这些代表了第一个定义的研究它在常见的神经性人类病毒感染的发病机理中的作用。在AIM 1中，我们将确定如何 LRRK2与NLRP3，HSV-1感染中的临界炎症适配器相关联以及如何中的突变 LRRK2在HSV-1感染的背景下改变了炎症体信号传导。我们将通过使用在炎性体信号传导的翻译模型中，有针对性的诱变和通过研究炎症体 HSV-1感染细胞系后稳定表达LRRK2突变体的激活。对于AIM 2，我们将确定 LRRK2如何使用LRRK2转基因小鼠和小鼠与HSV-1的炎性体反应改变炎症基因破坏。此外，PI将获得重要的技能和专业知识，以研究对HSV-1和其他疱疹病毒的先天免疫反应。这些学习对象将完成通过正式的课程，科学编程以及病毒和鼠专家的直接精神制作免疫学，疱疹病毒和生物统计学。拟议的职业发展计划和研究目标将作为研究疱疹病毒之间的相互作用的独立研究人员提供职业的途径和先天免疫系统。