Role of type 1 IFN in eye infection

1 型干扰素在眼部感染中的作用

• 批准号: 10732600
• 负责人: HOMAYON GHIASI
• 金额: $ 47.05万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732600
• 关键词: Affect; Apoptotic; Autophagocytosis; Binding; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Code; Complex; Cytokine Receptor Binding; Data; Development; Disease; Down-Regulation; Encephalitis; Environment; Event; Eye Infections; Eye diseases; Family; Genes; Herpes Labialis; Herpesvirus 1; Human; IFNAR1 gene; Immune response; In Vitro; Individual; Induction of Apoptosis; Infection; Infection prevention; Interferon Type I; Interferon alpha; Interferons; Latent virus infection phase; Lesion; Maps; Mediating; Modeling; Mus; Natural Killer Cells; Neurons; Nuclear; Pharyngitis; Phenotype; Play; Predisposition; Prevalence; Preventive; Primary Infection; Process; Production; Proteins; Public Health; Publishing; RNA; Recurrence; Recurrent disease; Regulation; Role; Signal Transduction; Simplexvirus; Site; Structure of trigeminal ganglion; System; Testing; Therapeutic; Transcript; Untranslated RNA; Vaccines; Virus; Virus Diseases; Virus Latency; Virus Replication; Wild Type Mouse; combinatorial; cytokine; design; genital herpes; in vivo; innovation; latency associated transcript; latent persistent infection; member; mortality; mouse model; neuron loss; pathogenic virus; prevent; promoter; protein function; reactivation from latency; recombinant virus; recurrent infection; response; secondary infection; vaccine development

ABSTRACT HSV-1 infection is a leading cause of eye disease and genital herpes but no HSV-1 vaccines have shown efficacy in humans. It elicits only a partially protective immune response and can establish persistent latent infections virus in neurons. Induction of type I interferons (IFNs) is an early, pivotal host response to most pathogenic viruses that limits viral replication, induces apoptosis/autophagy of infected cells, and mobilizes other immune responses. Although strategic circumvention of IFN responses is a hallmark of many viruses, it has not been fully defined in HSV-1 infections. Using recombinant viruses to dissect of the roles of individual cytokines in the context of the complex in vivo immune response environment, we have generated compelling preliminary data that indicate that circumvention of the type 1 IFN response plays a key role in both primary HSV-1 infection and subsequent induction of latency in mouse models of ocular infection and implicate the latency-associated transcript (LAT) of HSV-1 in modulation of the effects. IFN and IFN transcripts are significantly downregulated in the trigeminal ganglia (TG) of wild-type mice after ocular infection with LAT(+) virus as compared with LAT(-) virus. HSV-1 recombinant viruses expressing anti-apoptotic genes in place of LAT restore the LAT(+) survival phenotype to IFNAR1-/- infected mice, which are more susceptible to HSV-1 infection than wt mice. These activities of LAT map to an 811 bp region of LAT, which encodes small non- coding RNAs (sncRNAs). These and other data suggest a highly innovative hypothetical model in which HSV-1 LAT promotes HSV-1 evasion of clearance by the IFN system during both primary ocular infection and reactivation in the TG by: (i) Suppressing the production of IFN2 and/or IFN; and (ii) Limiting the apoptotic effects of IFN production. This hypothesis will be tested in mouse models by: (1) Determining if HSV-1 down- regulation of IFN2 and IFN, but not IFN, affects primary infection, establishment of latency, and reactivation in the TG after ocular HSV-1 infection; fine mapping of the regions of LAT involved in these processes; and analysis of the binding of the sncRNAs to IFN2 and IFN promoters in vitro; (2) Identification of the specific roles of LAT in protecting against infection in IFNAR1-/- mice through analysis of apoptosis induction and interference with replication together with fine-mapping of the regions of LAT that mediate these effects; and (3) Analysis of the differential and combinatorial roles of LAT-dependent IFN2 and IFN regulation in latency- reactivation and primary HSV-1 infection using IFN-/-, IFN2-/-, and IFN2-/-IFN-/- mice. The results generated will identify the primary mechanisms utilized by HSV-1 to evade the host IFN system and provide a basis for strategies that can be used to prevent infection and minimize recurrent disease.

抽象的 HSV-1感染是眼病和生殖器疱疹的主要原因，但没有显示HSV-1疫苗 它在人类中的功效。它仅引起部分保护的免疫反应，并可以建立持续的潜在 神经元中的感染病毒。 I型干扰素（IFN）的诱导是对大多数的早期，关键的主机响应 限制病毒复制，诱导感染细胞的凋亡/自噬的致病病毒，并动员 其他免疫反应。尽管IFN反应的战略圈子是许多病毒的标志，但 在HSV-1感染中尚未完全定义。使用重组病毒剖析个体的作用 在复杂的体内免疫反应环境的背景下，细胞因子，我们产生了引人注目的 表明规避1型IFN响应的初步数据在这两个初级中都起着关键作用 HSV-1感染以及随后在眼部感染小鼠模型中的潜伏期诱导，并暗示 HSV-1的延迟相关转录本（LAT）在调节效果中。 IFN和IFN成绩单是 眼部感染LAT（+）的野生型小鼠的三叉神经节（TG）中显着下调 与LAT（ - ）病毒相比，病毒。 HSV-1重组病毒表达抗凋亡基因代替 LAT将LAT（+）生存表型恢复为IFNAR1 - / - 感染小鼠，它们更容易受到HSV-1的影响 感染比WT小鼠。 LAT映射到LAT的811 bp区域的这些活动，该区域编码小的非非 - 编码RNA（SNCRNA）。这些数据和其他数据提出了一个高度创新的假设模型，其中HSV-1 LAT促进了原发性眼感染和 TG中的重新激活：（i）抑制IFN2和/或IFN的产生； （ii）限制凋亡 IFN产生的影响。该假设将在小鼠模型中通过：（1）确定HSV-1是否下降 - IFN2和IFN的调节，但不影响IFN，会影响原发性感染，延迟的建立和重新激活 在眼部HSV-1感染后的TG中；对这些过程涉及的LAT区域的精细映射；和 分析SNCRNA与IFN2和IFN启动子的结合； （2）识别特定 通过分析凋亡诱导和 干扰复制，以及介导这些效果的LAT区域的精细映射；和 （3）分析LAT依赖性IFN2和IFN调节的差异和组合作用 使用IFN-/ - ，IFN2 - / - 和IFN2 - / - IFN-/ - 小鼠使用重新激活和原发性HSV-1感染。结果 生成的将确定HSV-1使用的主要机制来逃避主机IFN系统并提供 可用于防止感染和最大程度减少复发性疾病的策略的基础。