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: 10576901
• 负责人: Cooper Kincaid Hayes
• 金额: $ 5.27万
• 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/10576901
• 关键词: AIM2 gene; Acyclovir; Address; Adult; Age; Antiviral Response; Apoptosis; Brain; Central Nervous System; Complex; DNA; Dangerousness; Data; Dependence; Development; Disease; Disease Outcome; Encephalitis; Equilibrium; Experimental Autoimmune Encephalomyelitis; Herpes Simplex Infections; Herpes encephalitis; Herpesvirus 1; IFNAR1 gene; IL18 gene; Immune; Immune response; Immunologic Factors; Immunotherapeutic agent; In Vitro; Incidence; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Interferon Receptor; Interferon Type I; Interferon Type II; Interleukin-1; Interleukin-1 beta; Ischemic Stroke; Knockout Mice; Live Birth; Lytic; Morbidity - disease rate; Multiprotein Complexes; Mus; Neonatal; 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; Signaling Protein; Simplexvirus; Stimulus; System; United States; Viral Encephalitis; Viral Pathogenesis; Virus Diseases; Virus Replication; Work; age related; cytokine; driving force; experimental study; immune cell infiltrate; immunopathology; improved; in vivo; insight; interest; interferon alpha receptor; marenostrin; mortality; mouse model; neonatal brain; neonatal infection; neonatal mice; 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.

项目摘要 成年人中的单纯疱疹病毒（HSV）感染通常是亚临床的，但新生儿的感染通常会导致 散布疾病或脑炎的严重发病率和死亡率。相比之下，HSV脑炎（HSE） 在成年人中很少见，其中100万分之一。这种敏感性差异的准确原因和 结果尚不清楚，但是新生儿大脑和成年大脑的免疫反应差异 尽管许多研究集中在限制病毒的先天免疫因素上 复制，很少有人检查了在感染过程中可能有害的促炎途径。 炎症小体是一个多蛋白信号平台 炎性细胞因子白介素1β（IL-1β）。刺激炎症模式识别 受体，炎性体复合物寡聚并激活pro-caspase-1，从而裂解 IL-1β。最佳特征炎症小体是NLRP3炎症小体，因为它的激活范围很广 刺激，但其他几种炎症体被表征，已知会被HSV激活 体外。已知其他几种病毒感染被NLRP3产生的注射遗忘了 炎症。我的初步数据表明，一个或多个炎性体复合物有助于 HSE的鼠模型中的死亡率。我假设炎症体产生的炎症 有助于单纯疱疹脑炎的发病机理。 I型Interferon（IFN）信号传导的不足可能有助于增加 对HSV感染的敏感性。重要的是，I型干扰素途径充当IL-1β的负调节剂 生产和炎症激活以防止危险的炎症水平。容量下降 对于新生儿中的I型IFN信号传导表明HSV期间炎症体的负调节不足 感染。根据我的初步数据表明，IL-1β在更新的程度上更新 感染期间的新生儿比成人。因此，我还假设I类IFN缺乏 新生儿中的信号导致新生儿和新生儿之间的炎性体激活差异 HSV脑炎期间的成年人。将HSE的鼠模型与遗传删除的小鼠使用 炎性组成分，我将阐明有助于发病机理的特定炎症。我会 表征所得的细胞因子剖面和免疫细胞浸润，它们是在下游下游产生的 感染过程中的炎症。最后，我将确定炎性体激活的程度 使用IFN受体敲除小鼠受I型IFN系统调节。这些实验将推动我们的 了解HSV脑炎的发病机理以及导致更严重疾病的因素 在新生儿。