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 成人的单纯疱疹病毒(HSV)感染通常是亚临床的，但新生儿的感染通常会导致 播散性疾病或脑炎的严重发病率和死亡率。相比之下，单纯疱疹病毒性脑炎(HSE) 在成人中罕见，发病率为1/1,000,000。造成这种敏感度差异的确切原因是 结果尚不清楚，但新生儿大脑和成人大脑免疫反应的差异已经 被牵连了。尽管许多研究都集中在限制病毒的先天免疫因素上 在复制方面，很少有人研究在感染过程中可能有害的促炎途径。这个 炎症体是一个多蛋白质信号平台，导致前体细胞的加工和释放。 炎性细胞因子白介素1β(IL-1β)。在刺激炎症体模式识别时 受体，炎症体复合体寡聚并激活原caspase-1，允许切割 IL-1β。最具特征的炎症体是NLRP3炎症体，因为它具有广泛的激活范围 刺激，但其他几个炎症体已被表征，并已被已知激活HSV在 体外培养。已知其他几种病毒感染会因NLRP3引起的炎症而恶化 炎症者。我的初步数据表明，一个或多个炎症体复合体有助于 HSE小鼠模型的死亡率。我推测炎症小体引起的炎症 与单纯疱疹病毒性脑炎的发病机制有关。 新生儿大脑中I型干扰素(干扰素)信号的缺陷可能是导致 对HSV感染的易感性。重要的是，I型干扰素途径作为IL-1β的负调节因子 产生和激活炎症小体，以防止达到危险程度的炎症。减少的运力 对于新生儿中的I型干扰素信号，提示在HSV期间缺乏对炎症体的负调控 感染。因此，我的初步数据表明，IL-1β在更大程度上被上调 新生儿在感染期间比成人更容易感染。因此，我还假设I型干扰素的缺陷 新生儿体内的信号转导导致新生儿和新生儿之间炎症体激活的差异 成人在单纯疱疹病毒性脑炎期间。使用HSE的小鼠模型，其中小鼠的基因缺失 炎性小体成分，我将阐明参与发病机制的具体炎性小体。这就做 描述由此产生的细胞因子谱和免疫细胞渗透，这些细胞因子和免疫细胞渗透产生于 感染时有炎症者。最后，我将确定炎症小体激活的程度 利用干扰素受体基因敲除小鼠的I型干扰素系统进行调节。这些实验将推进我们的 对单纯疱疹病毒性脑炎发病机制及致病因素的认识 在新生儿身上。