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

• 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
• 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

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.

项目总结 与成年人相比，新生儿的大脑特别容易受到各种病原体的影响，而这一点 例如感染了单纯疱疹病毒1型(HSV-1)，这是病毒最常见的原因 脑炎。大多数感染了HSV-1的新生儿会继续患上严重的疾病，包括病毒 传播和脑炎，而成年人感染通常会导致无症状 获得性或良性黏膜感染。尽管感染了HSV-1，成人中的HSV脑炎仍然很少见 这一人群的血清阳性率为50-80%。成人和成人之间显著不同的结果 感染单纯疱疹病毒的新生儿中枢神经系统易感性存在年龄相关性差异 基于宿主因素的神经系统(CNS)疾病。新生儿免疫系统的相对不成熟是 然而，这通常与他们对HSV和其他嗜神经性病毒的总体易感性增加有关， 他们对病毒性脑炎易感性增加的确切原因尚不清楚。这个 对新生儿发病机制的不完全理解仍然是改善的关键障碍 单纯疱疹病毒性脑炎后的存活率和神经学转归。 在这项提议中，我们计划研究大脑中负责 新生儿与成人单纯疱疹病毒病易感性及严重程度的差异我们将在我们的 以前未获资助的工作，以了解宿主反应在确定病毒嗜性中的作用 脑，神经胶质细胞在HSV-1感染中的作用，以及I型对血脑屏障的调节 新生儿感染过程中的干扰素信号传递。HSV-1和宿主的抗病毒反应已经 然而，经常在神经元感染的背景下进行研究，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显示，星形细胞 新生儿脑内感染除神经元外，与I型干扰素反应有显著差异 在这两个年龄段之间。我们假设星形胶质细胞和小胶质细胞对病毒的贡献 单纯疱疹病毒性脑炎后的复制和存活与年龄有关。我们提议的研究将证明 星形胶质细胞和小胶质细胞特异性I型干扰素信号在单纯疱疹病毒致病中的作用及其机制 这种反应会随着发育年龄的不同而变化。单纯疱疹病毒性脑炎常发生在 新生儿中的播散性疾病，我们还计划研究I型干扰素在调节 感染期间血脑屏障及其对单纯疱疹病毒的贡献扩散到大脑。我们实验室的初步数据显示 在播散性疾病期间，I型干扰素治疗可提高存活率并减少HSV神经侵袭。在……里面 在这项提议中，我们将探讨新生儿血脑屏障调节的先天免疫机制 并阐明了免疫调节治疗改善这一年龄组预后的可能性。