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: 9890025
• 负责人: Richard M Longnecker
• 金额: $ 32.9万
• 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/9890025
• 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; Expression Profiling; 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.

项目摘要 与成人相比，新生儿的大脑特别容易受到各种病原体的影响， 在感染1型单纯疱疹病毒（HSV-1）后举例说明， 脑炎大多数感染HSV-1的新生儿将继续患有严重的疾病，包括病毒感染。 传播和脑炎，而在成人人群中感染通常导致无症状的 获得或良性粘膜感染。成人HSV脑炎仍然罕见，尽管HSV-1 该人群的血清阳性率为50-80%。成年人和成年人之间的显著差异 HSV感染后的新生儿对中枢神经系统的易感性存在年龄依赖性差异， 中枢神经系统（CNS）疾病的基础上，主机因素。新生儿免疫系统相对不成熟， 通常与它们对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然不明。的 对新生儿群体发病机制的不完全理解仍然是改善新生儿疾病的关键障碍。 HSV脑炎后的生存率和神经学结局。 在这项提案中，我们计划研究大脑中负责 新生儿和成人之间HSV疾病的易感性和严重程度的差异。我们将建立在我们的 以前没有资助的工作，以了解在确定病毒的嗜性内的宿主反应的作用， 脑，胶质细胞对HSV-1感染的贡献，以及I型病毒对血脑屏障（BBB）的调节 干扰素（IFN）信号在新生儿感染期间。HSV-1和宿主的抗病毒反应一直是 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 在新生儿脑内感染除神经元外，I型IFN反应差异显著 两个年龄组之间。我们假设星形胶质细胞和小胶质细胞对病毒感染的贡献可能与它们的免疫功能有关。 HSV脑炎后的复制和存活是年龄依赖性的。我们提出的研究将证明 I型IFN信号在星形胶质细胞和小胶质细胞中对HSV发病机制的作用，以及如何 这种反应在不同的发育年龄中会发生变化。HSV脑炎通常发生在 我们还计划研究I型干扰素在调节新生儿播散性疾病中的作用， 血脑屏障在感染期间有助于HSV扩散到脑部。我们实验室的初步数据显示 I型干扰素治疗可提高生存率并减少HSV在播散性疾病中的神经侵袭。在 在这个提议中，我们将继续研究新生儿BBB调节的先天免疫机制 大脑，并阐明免疫调节治疗的潜力，以改善该年龄组的结果。