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: 10349586
• 负责人: Cooper Kincaid Hayes
• 金额: $ 4.33万
• 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/10349586
• 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; 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 单纯疱疹病毒（HSV）感染在成人中通常是亚临床的，但在新生儿中感染通常导致 传播性疾病或脑炎导致的严重发病和死亡。HSV脑炎（HSE） 在成年人中很少见，发病率为百万分之一。这种敏感性差异的确切原因， 结果尚不清楚，但新生儿大脑和成人大脑中免疫反应的差异 被牵连。虽然许多研究都集中在先天免疫因素，限制病毒 复制，很少有人检查可能是有害的感染过程中的促炎途径。的 炎性小体是一个多蛋白信号平台，导致前体的加工和释放， 炎性细胞因子白细胞介素-1 β（IL-1β）。在刺激炎性小体模式识别后， 受体时，炎性体复合物寡聚化并激活胱天蛋白酶原-1，允许切割 IL-1β。最好表征的炎性小体是NLRP 3炎性小体，由于其广泛的活化范围， 刺激，但几种其他炎性小体已被表征，并已知在感染中被HSV激活。 体外已知其他几种病毒感染会因NLRP 3产生的炎症而恶化 炎性小体我的初步数据表明，一个或多个炎性复合体有助于 HSE小鼠模型中的死亡率。我假设炎性小体产生的炎症 有助于单纯疱疹脑炎的发病机制。 新生儿脑中I型干扰素（IFN）信号传导的缺乏可能导致新生儿脑中I型干扰素（IFN）信号传导的增加。 HSV感染的易感性。重要的是，I型干扰素途径作为IL-1β的负调节剂 产生和炎性体激活，以防止危险的炎症水平。能力下降 对于新生儿中的I型IFN信号转导，提示HSV感染期间炎性小体缺乏负调节。 感染因此，我的初步数据表明，IL-1β上调的程度更大， 新生儿在感染期间比成人。因此，我也假设I型干扰素缺乏 新生儿中的信号传导导致新生儿之间炎性小体活化的差异， 成人HSV脑炎使用HSE小鼠模型，其中小鼠基因缺失 炎性小体成分，我将阐明具体的炎性小体，有助于发病机制。我会 表征所得到的细胞因子谱和免疫细胞浸润，所述细胞因子谱和免疫细胞浸润是在细胞因子的下游产生的。 在感染期间的炎性小体。最后，我将确定炎性小体激活的程度， 使用IFN-受体敲除小鼠通过I型IFN系统调节。这些实验将推动我们的 了解HSV脑炎的发病机制和导致更严重疾病的因素 在新生儿中。