An Age-Dependent Role of the Inflammasome in the Pathogenesis of HSV Encephalitis

炎症小体在 HSV 脑炎发病机制中的年龄依赖性作用

• 批准号: 9911437
• 负责人: Cooper Kincaid Hayes
• 金额: $ 5.05万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911437
• 关键词: AIM2 gene; Acyclovir; Address; Adult; Age; Antiviral Response; Apoptosis; Brain; CASP1 gene; Complex; DNA; Dangerousness; Data; Dependence; Development; Disease; Disease Outcome; Encephalitis; Equilibrium; Experimental Autoimmune Encephalomyelitis; Herpes encephalitis; Herpesvirus 1; Immune; Immune response; Immunologic Factors; Immunotherapeutic agent; In Vitro; Incidence; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Interferon Receptor; Interferon Type I; Interferons; Interleukin-1; Interleukin-1 beta; Interleukin-18; Ischemic Stroke; Knockout Mice; Live Birth; Lytic; Morbidity - disease rate; Multiprotein Complexes; Mus; Neonatal; Neuraxis; Neurodegenerative Disorders; Neurologic; Newborn Infant; Outcome; Pathogenesis; Pathology; Pathway interactions; Pattern recognition receptor; Phenotype; Predisposition; Process; Production; Proteins; Regulation; Role; Severity of illness; Signal Transduction; Simplexvirus; Stimulus; System; Tumor-infiltrating immune cells; United States; Viral Encephalitis; Viral Pathogenesis; Virus Diseases; Virus Replication; Work; age related; cytokine; driving force; experimental study; immunopathology; improved; in vivo; insight; interest; interferon alpha receptor; marenostrin; mortality; mouse model; neonatal brain; neonatal infection; neonate; neuroinflammation; pathogen; prevent; response; seropositive; targeted treatment

Project Summary Herpes simplex virus (HSV) infection in adults is often subclinical, but infection in neonates commonly leads to severe morbidity and mortality from disseminated disease or encephalitis. By contrast, HSV encephalitis (HSE) is rare in adults with an incidence of 1 in 1,000,000. The precise reason for this difference in susceptibility and outcomes is unknown, but differences in the immune responses in the neonatal brain and the adult brain have been implicated. Although numerous studies have focused on innate immune factors that restrict viral replication, few have examined the pro-inflammatory pathways that may be detrimental during infection. The inflammasome is a multi-protein signaling platform that leads to the processing and release of the pro- inflammatory cytokine interleukin-1β (IL-1β). Upon stimulation of an inflammasome pattern recognition receptor, the inflammasome complex oligomerizes and activates pro-caspase-1, allowing for the cleavage of IL-1β. The best characterized inflammasome is the NLRP3 inflammasome due to its wide range of activating stimuli, but several other inflammasomes have been characterized and are known to be activated by HSV in vitro. Several other viral infections are known to be worsened by the inflammation generated by the NLRP3 inflammasome. My preliminary data suggests that one or more inflammasome complexes contribute to mortality in a murine model of HSE. I hypothesize that the inflammation generated by the inflammasome contributes to the pathogenesis of herpes simplex encephalitis. A deficiency in type I interferon (IFN) signaling in the neonatal brain likely contributes to increased susceptibility to HSV infection. Importantly, the type I interferon pathway acts as a negative regulator of IL-1β production and inflammasome activation to prevent dangerous levels of inflammation. The decreased capacity for type I IFN signaling in the neonate suggests a lack of negative regulation of the inflammasome during HSV infection. Accordingly, my preliminary data suggests that IL-1β is upregulated to a greater degree in the neonate during infection than in the adult. Therefore, I also hypothesize that a deficiency in Type I IFN signaling in the neonate contributes to differences in inflammasome activation between neonates and adults during HSV encephalitis. Using a murine model of HSE with mice genetically deleted for inflammasome components, I will elucidate the specific inflammasomes that contribute to pathogenesis. I will characterize the resulting cytokine profile and immune cell infiltrate that are generated downstream of the inflammasome during infection. Finally, I will determine the extent to which inflammasome activation is regulated by the type I IFN system using IFN-receptor knockout mice. These experiments will advance our understanding of the pathogenesis of HSV encephalitis and the factors that contribute to more severe disease in neonates.

项目概要 成人单纯疱疹病毒 (HSV) 感染通常是亚临床的，但新生儿感染通常会导致 相比之下，传播性疾病或脑炎导致严重的发病率和死亡率。 成人中罕见，发病率为百万分之一。造成这种易感性差异的确切原因是 结果尚不清楚，但新生儿大脑和成人大脑的免疫反应存在差异 尽管许多研究都集中在限制病毒的先天免疫因素上。 复制过程中，很少有人研究过感染过程中可能令人痛苦的促炎途径。 炎性小体是一种多蛋白信号传导平台，可导致前体的加工和释放 炎症细胞因子白细胞介素 1β (IL-1β) 受到炎症小体模式识别的刺激。 受体时，炎性体复合物寡聚并激活 pro-caspase-1，从而裂解 IL-1β 的最佳特征是 NLRP3 炎症体，因为它具有广泛的激活作用。 刺激，但其他几种炎性小体已被表征并且已知在以下情况下被 HSV 激活： 已知其他几种病毒感染会因 NLRP3 产生的炎症而恶化。 我的初步数据表明，一种或多种炎性体复合物有助于 在 HSE 小鼠模型中，我对炎症小体产生的炎症感到困惑。 有助于单纯疱疹脑炎的发病机制。 新生儿大脑中 I 型干扰素 (IFN) 信号传导的缺陷可能导致新生儿大脑中 I 型干扰素 (IFN) 信号的增加 重要的是，I 型干扰素途径充当 IL-1β 的负调节因子。 产生和激活炎症体以防止危险水平的炎症的能力下降。 新生儿 I 型 IFN 信号传导表明 HSV 期间缺乏炎症小体的负调节 因此，我的初步数据表明，IL-1β 在感染中更大程度地上调。 新生儿感染期间的感染率高于成人，因此，我也认为 I 型 IFN 缺乏。 新生儿的信号传导导致新生儿和新生儿之间炎症小体激活的差异 使用 HSE 小鼠模型，对小鼠进行基因删除。 炎症小体成分，我将阐明有助于发病机制的特定炎症小体。 表征产生的细胞因子谱和免疫细胞浸润的下游产生 最后，我将确定感染期间炎症小体的激活程度。 使用 IFN 受体敲除小鼠受 I 型 IFN 系统调节这些实验将推进我们的研究。 了解 HSV 脑炎的发病机制以及导致更严重疾病的因素 在新生儿中。