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Role of Host Cell Factors in Newborn Herpes Simplex Virus (HSV) Encephalitis

宿主细胞因子在新生儿单纯疱疹病毒 (HSV) 脑炎中的作用

基本信息

批准号：
10133167
负责人：
Richard M Longnecker
金额：
$ 32.82万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133167
关键词：
Address Adult Age Antiviral Response Astrocytes Benign Biological Assay Birth Blood - brain barrier anatomy Brain Cell Separation Cells Cellular Tropism Central Nervous System Diseases Central Nervous System Viral Diseases Child Clustered Regularly Interspaced Short Palindromic Repeats Data Development Disease Encephalitis Exhibits Flow Cytometry Fluorescein Gene Expression Genetic study Herpesvirus 1 IFNAR1 gene Immune response Immunofluorescence Immunologic In Vitro Incidence Infection Infiltration Innate Immune Response Integration Host Factors Interferon Type I Interferon-alpha Interferon-beta Interferons Knockout Mice Mediating Messenger RNA Microglia Microspheres Modeling Morbidity - disease rate Mucous Membrane Mus Mutation Neonatal Neonatal Mortality Neuraxis Neuroglia Neurologic Neurological outcome Neurons Neurotropism Newborn Infant Outcome Pathogenesis Pathway interactions Play Population Predisposition Primary Cell Cultures Production Proteins Role Seroprevalences Severities Severity of illness Signal Pathway Signal Transduction Simplexvirus Structure of choroid plexus Survivors Target Populations Tropism United States Viral Viral Encephalitis Viral Pathogenesis Virus Diseases Virus Replication Work age group age related base blood-brain barrier permeabilization cytokine experimental study high risk immunomodulatory therapies improved improved outcome innate immune mechanisms insight mortality mouse model neonatal immune system neonatal infection neonatal morbidity neurodevelopment neurotropic neurotropic virus pathogen prevent receptor recombinase-mediated cassette exchange response small hairpin RNA survival outcome virus tropism

项目摘要

PROJECT SUMMARY The newborn brain is uniquely susceptible to a wide range of pathogens compared to the adult, and this is exemplified following infection with herpes simplex virus type-1 (HSV-1), the most common cause of viral encephalitis. The majority of newborns infected with HSV-1 will go on to have severe disease, including viral dissemination and encephalitis, whereas infection in the adult population typically results in asymptomatic acquisition or benign mucosal infection. HSV encephalitis in the adult remains rare despite a HSV-1 seroprevalence of 50-80% in this population. The significantly different outcomes between adults and newborns following HSV infection suggest an age-dependent difference in susceptibility to central nervous system (CNS) disease based on host factors. A relative immaturity of the neonatal immune system is commonly implicated in their overall increased susceptibility to HSV and other neurotropic viruses, however, the precise reasons underlying their increased susceptibility to viral encephalitis remain unknown. The incomplete understanding of pathogenesis in the neonatal population remains as a critical barrier to improving survival and neurologic outcomes following HSV encephalitis. In this proposal, we plan to investigate the innate immune mechanisms in the brain responsible for differences in susceptibility and severity of HSV disease between the newborn and adult. We will build on our previously unfunded work to understand the role of the host response in determining viral tropism within the brain, the contribution of glial cells to HSV-1 infection, and modulation of the blood brain barrier (BBB) by type I interferon (IFN) signaling in the newborn during infection. HSV-1 and the host antiviral response has been frequently studied in the context of neuronal infection, however, there is an emerging role for astrocytes and microglia in the pathogenesis of viral encephalitis. Preliminary data from our lab demonstrates astrocytic infection in the newborn brain in addition to neurons, and significant differences in the type I IFN response between the two age groups. We hypothesize that the contribution of astrocytes and microglia to viral replication and survival following HSV encephalitis is age-dependent. Our proposed studies will demonstrate the contribution of type I IFN signaling specifically in astrocytes and microglia to HSV pathogenesis, and how this response changes through different developmental ages. HSV encephalitis often occurs in the context of disseminated disease in the newborn, and we also plan to investigate the role of type I IFN in modulating the BBB during infection and its contribution to HSV spread to the brain. Preliminary data from our lab suggests that type I IFN treatment improves survival and reduces HSV neuroinvasion during disseminated disease. In this proposal, we will pursue the innate immune mechanisms that underlie BBB modulation in the newborn brain, and elucidate the potential of immunomodulatory therapy to improve outcomes in this age group.

项目概要与成人相比，新生儿大脑特别容易受到多种病原体的影响，这以感染 1 型单纯疱疹病毒 (HSV-1) 为例，该病毒是病毒感染的最常见原因脑炎。大多数感染 HSV-1 的新生儿会发展为严重疾病，包括病毒性疾病传播和脑炎，而成年人群中的感染通常会导致无症状获得性或良性粘膜感染。尽管存在 HSV-1，但成人 HSV 脑炎仍然罕见该人群的血清阳性率为 50-80%。成人和成人之间的结果存在显着差异 HSV 感染后的新生儿提示中枢神经系统易感性存在年龄依赖性差异基于宿主因素的系统（CNS）疾病。新生儿免疫系统相对不成熟通常与他们对 HSV 和其他嗜神经病毒的总体易感性增加有关，然而，他们对病毒性脑炎的易感性增加的确切原因仍不清楚。这对新生儿发病机制的不完全了解仍然是改善新生儿疾病的关键障碍 HSV 脑炎后的生存和神经系统结果。在这项提案中，我们计划研究大脑中负责的先天免疫机制新生儿和成人之间 HSV 疾病的易感性和严重程度存在差异。我们将在我们的基础上再接再厉以前没有资助的工作来了解宿主反应在确定病毒趋向性方面的作用脑、神经胶质细胞对 HSV-1 感染的贡献以及 I 型对血脑屏障 (BBB) 的调节感染期间新生儿中的干扰素 (IFN) 信号传导。 HSV-1 和宿主的抗病毒反应经常在神经元感染的背景下进行研究，然而，星形胶质细胞和小胶质细胞在病毒性脑炎发病机制中的作用。我们实验室的初步数据表明星形胶质细胞除神经元外，新生儿大脑中也存在感染，并且 I 型 IFN 反应存在显着差异两个年龄段之间。我们假设星形胶质细胞和小胶质细胞对病毒的贡献 HSV 脑炎后的复制和存活与年龄有关。我们提出的研究将证明 I 型 IFN 信号传导（特别是在星形胶质细胞和小胶质细胞中）对 HSV 发病机制的贡献，以及如何这种反应会随着不同的发育年龄而变化。 HSV 脑炎通常发生在以下情况新生儿播散性疾病，我们还计划研究 I 型 IFN 在调节新生儿播散性疾病中的作用感染期间的 BBB 及其对 HSV 传播到大脑的贡献。我们实验室的初步数据表明 I 型 IFN 治疗可提高生存率并减少播散性疾病期间的 HSV 神经侵袭。在在这个提案中，我们将研究新生儿 BBB 调节背后的先天免疫机制大脑，并阐明免疫调节疗法改善该年龄组预后的潜力。