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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：
10608136
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/10608136
关键词：
Adult Alleles Bacterial Infections Binding Biometry Blindness Cell Death Cell Line Cells Central Nervous System Cornea Crohn&apos s disease Cutaneous Data Developed Countries Development Plans Disease Disease model Encephalitis Etiology Eye Family Flow Cytometry General Population Genes Herpes encephalitis Herpes stromal keratitis Herpesviridae Herpesvirus 1 High Prevalence Human IL18 gene Immune Immune response Immunocompromised Host Immunohistochemistry Immunologics Immunology Infection Infection Control Inflammasome Inflammation Inflammatory Innate Immune Response Innate Immune System Integration Host Factors Interleukins Intervention Knockout Mice Knowledge LRRK2 gene Learning Leprosy Lesion Life Macrophage Malignant Neoplasms Measurable Measures Mediating Mentorship Modeling Morbidity - disease rate Multiprotein Complexes Mus Mutagenesis Mutation Natural Immunity Organ Transplantation Outcome Parkinson Disease Pathogenesis Pathogenicity Pathology Pathway interactions Population Production Regulation Research Research Personnel Role Severities Signal Pathway Signal Transduction Simplexvirus Skin System Testing Tissues Training Transfection Transgenic Mice United States Vaccines Viral Viral Encephalitis Viral Pathogenesis Virulence Virus Virus Diseases Virus Replication career career development cell type chemokine cytokine immune activation immune cell infiltrate in vivo marenostrin mortality mouse LRRK2 protein mouse model mutant neurotropic neurotropic virus novel novel therapeutics outcome disparities pathogen 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.

项目总结在美国，单纯疱疹病毒1型(HSV-1)感染了超过一半的成年人，是病毒性脑炎和传染性失明的主要原因。然而，宿主因素对最大的 HSV-1的严重表现尚不清楚。炎性小体--一种新近发现的先天抗病毒药物免疫防御和产生两种炎症体细胞因子(IL-1和IL-18)是至关重要的在HSV-1的控制和发病机制上。然而，在HSV-1感染期间炎性小体是如何被调节的人们对此知之甚少。最近，富含亮氨酸的重复蛋白激酶2(LRRK2)被认为是一种可能的调节因子。炎症小体信号。LRRK2已经被广泛研究，因为特定的等位基因与帕金森氏症、克罗恩病、癌症和麻风病。尽管与疾病有关联，但准确的 LRRK2的功能及其如何介导疾病尚不清楚。在免疫反应中发挥作用的证据包括LRRK2在免疫细胞上高表达，在感染后上调，并被最近发现可以调节NLRC4炎症体对细菌感染的反应。我们最近我们的初步数据表明，NLRP3在HSV-1激活炎症体的过程中起关键作用 LRRK2增强了NLRP3信号转导。我们发现常见的LRRK2突变G2019S增强了HSV- 1在不改变病毒复制的情况下对小鼠进行病理学检查。这些结果表明LRRK2在炎症体信号与HSV-1致病机制。我们假设LRRK2调节炎症小体 HSV-1感染和G2019S突变进一步增强炎症体的信号转导体内激活，导致HSV-1后眼睛、皮肤和中枢神经系统(CNS)更严重的病理感染。LRRK2在人类病毒感染中还没有被研究过，这些研究是第一次确定它在一种常见的嗜神经性人类病毒感染的发病机制中所起的作用。在目标1中，我们将确定如何 LRRK2与NLRP3有关，NLRP3是HSV-1感染中的关键炎症体接头，以及 LRRK2在HSV-1感染的背景下改变炎症体信号转导。我们将通过使用炎症体信号转导模型中的靶向突变及炎症体研究 HSV-1感染稳定表达LRRK2突变体的细胞系的激活。对于目标2，我们将确定 LRRK2转基因小鼠和携带LRRK2基因的小鼠如何改变HSV-1的炎症体应答炎症体基因中断。此外，PI将获得必要的关键技能和专业知识来学习对HSV-1和其他疱疹病毒的先天免疫反应。这些学习目标将会实现通过正规课程、科学规划以及病毒和鼠类方面专家的直接指导免疫学、疱疹病毒学和生物统计学。拟议的职业发展计划和研究目标将作为一名研究疱疹病毒之间相互作用的独立调查者，提供一条职业道路和先天免疫系统。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children.

DOI：
10.1172/jci171729
发表时间：
2023-11-01
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Andargie, Temesgen E.;Roznik, Katerina;Redekar, Neelam;Hill, Tom;Zhou, Weiqiang;Apalara, Zainab;Kong, Hyesik;Gordon, Oren;Meda, Rohan;Park, Woojin;Johnston, Trevor S.;Wang, Yi;Brady, Sheila;Ji, Hongkai;Yanovski, Jack A.;Jang, Moon K.;Lee, Clarence M.;Karaba, Andrew H.;Cox, Andrea L.;Agbor-Enoh, Sean
通讯作者：
Agbor-Enoh, Sean

Discordant Antibody and T-Cell Responses to the Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant in Coronavirus Disease 2019 Messenger RNA Vaccine Recipients.

2019 年冠状病毒病 Messenger RNA 疫苗接种者对严重急性呼吸系统综合症冠状病毒 2 Omicron 变体的抗体和 T 细胞反应不一致。

DOI：
10.1093/cid/ciac305
发表时间：
2022
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
0
作者：
Woldemeskel,BezawitA;Garliss,CarolineC;Aytenfisu,TihitinaY;Johnston,TrevorS;Cox,AndreaL;Karaba,AndrewH;Blankson,JoelN
通讯作者：
Blankson,JoelN

Association of Frailty, Age, and Biological Sex With Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccine-Induced Immunity in Older Adults.