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，但尚未显示 HSV-1 疫苗 它对人类仅产生部分保护性免疫反应，并且可以建立持续的潜伏性免疫反应。 I 型干扰素 (IFN) 的诱导是宿主对大多数病毒的早期关键反应。 病原病毒，限制病毒复制，诱导受感染细胞凋亡/自噬，并动员 尽管战略性规避干扰素反应是许多病毒的一个特点，但它 使用重组病毒来剖析个体的作用尚未完全明确。 在复杂的体内免疫反应环境中的细胞因子，我们已经产生了令人信服的 初步数据表明，规避 1 型干扰素反应在原发性和 HSV-1 感染和随后在小鼠眼部感染模型中诱导潜伏期并暗示 HSV-1 的潜伏期相关转录本 (LAT) 对 IFNα 和 IFNβ 转录本的调节作用。 眼部感染 LAT(+) 后野生型小鼠的三叉神经节 (TG) 显着下调 病毒与表达抗凋亡基因的 LAT(-) 病毒相比。 LAT 恢复 IFNAR1-/- 感染小鼠的 LAT(+) 存活表型，这些小鼠更容易感染 HSV-1 LAT 的这些活性映射到 LAT 的 811 bp 区域，该区域编码小的非 这些和其他数据表明 HSV-1 是一个高度创新的假设模型。 LAT 促进 HSV-1 在原发性眼部感染和 通过以下方式重新激活 TG：(i) 抑制 IFNα2 和/或 IFNα 的产生；以及 (ii) 限制细胞凋亡； 该假设将通过以下方式在小鼠模型中进行检验：(1) 确定 HSV-1 是否下调。 IFNα2 和 IFNα（而非 IFNα）的调节影响原发感染、潜伏期的建立和重新激活 眼部 HSV-1 感染后的 TG 中参与这些过程的 LAT 区域的精细定位； （二）具体认定 通过分析细胞凋亡诱导和 IFNAR1-/- 小鼠的 LAT 在预防感染中的作用 干扰复制以及介导这些效应的 LAT 区域的精细映射； (3) 分析 LAT 依赖性 IFNα2 和 IFNα 调节在潜伏期中的差异和组合作用 使用 IFNα-/-、IFNα2-/- 和 IFNα2-/-IFNα-/- 小鼠进行再激活和原发性 HSV-1 感染。 生成的结果将识别 HSV-1 用于逃避宿主 IFN 系统的主要机制，并提供 为预防感染和减少疾病复发的策略奠定了基础。