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.

摘要 HSV-1感染是眼部疾病和生殖器疱疹的主要原因，但没有HSV-1疫苗显示 在人类中的功效。它只产生部分保护性免疫应答， 感染神经元中的病毒。I型干扰素（IFN）的诱导是对大多数免疫缺陷病毒的早期关键宿主应答。 限制病毒复制、诱导受感染细胞凋亡/自噬并动员 其他免疫反应。尽管策略性地规避IFN应答是许多病毒的标志，但它 在HSV-1感染中尚未完全确定。利用重组病毒剖析个体的作用 在复杂的体内免疫应答环境的背景下，我们已经产生了令人信服的 初步数据表明，1型干扰素反应的规避在原发性和非原发性肿瘤中起着关键作用， HSV-1感染和随后诱导小鼠眼部感染模型的潜伏期， HSV-1的潜伏相关转录物（LAT）在调节作用中的作用。IFN γ和IFN γ转录物是 LAT（+）眼部感染后野生型小鼠三叉神经节（TG）中的显著下调 与LAT（-）病毒相比，HSV-1重组病毒表达抗凋亡基因代替 LAT恢复了IFNAR 1-/-感染小鼠的LAT（+）存活表型，这些小鼠对HSV-1更敏感 感染率高于野生型小鼠。LAT的这些活性映射到LAT的811 bp区域，其编码小的非- 编码RNA（sncRNA）。这些和其他数据表明一个高度创新的假设模型，其中HSV-1 LAT促进HSV-1逃避IFN系统的清除， 通过以下方式在TG中重新激活：（i）抑制IFN γ 2和/或IFN γ 2的产生;和（ii）限制细胞凋亡， IFN生产的影响。该假设将通过以下方式在小鼠模型中进行测试：（1）确定HSV-1是否下降， IFN γ 2和IFN γ 2的调节，而不是IFN γ 3，影响原发感染，潜伏期的建立和再激活 在眼部HSV-1感染后的TG中;涉及这些过程的LAT区域的精细定位;以及 体外分析sncRNA与IFN γ 2和IFN γ 2启动子的结合;（2）特异性结合的鉴定 LAT在IFNAR 1-/-小鼠抗感染中的作用，通过分析细胞凋亡诱导和 干扰复制以及介导这些效应的LAT区域的精细定位;以及 (3)LAT依赖性IFN γ 2和IFN γ 2调节在潜伏期和潜伏期内的差异和组合作用的分析 使用IFN γ-/-、IFN γ 2-/-和IFN γ 2-/-IFN γ-/-小鼠的再活化和初次HSV-1感染。结果 所产生的将确定HSV-1逃避宿主IFN系统的主要机制，并提供一种新的方法， 这是可用于预防感染和尽量减少复发疾病的战略的基础。