Evaluation of innate antiviral responses on neuronal spread of HSV-1 infection

HSV-1 感染神经元传播的先天抗病毒反应评估

• 批准号: 10116272
• 负责人: Matthew P. Taylor
• 金额: $ 18万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116272
• 关键词: Address; Affect; Antiviral Agents; Antiviral Response; Axon; Axonal Transport; Benign; Brain; Cells; Data; Disease; Encephalitis; Epithelial; Evaluation; Foundations; Frequencies; Future; Genome; Goals; Herpes Labialis; IRF3 gene; Immunocompetence; Infection; Interferon Activation; Interferon-beta; Knowledge; Label; Lesion; Literature; Maintenance; Measures; Mediating; Methods; Modeling; NF-kappa B; Neurons; Peripheral; Phosphatidylinositide 3-Kinase Inhibitor; Plaque Assay; Play; Proteins; Publishing; Recurrence; Regulation; Role; Severity of illness; Simplexvirus; Testing; Viral; Virion; Virus Diseases; Virus Latency; Virus Replication; base; experimental study; improved; insight; latent infection; microscopic imaging; mortality; neuronal transport; neurotransmission; prevent; protein expression; transmission process; viral transmission

Antiviral responses play a critical role in the management of neuronal HSV-1 infections. Deficiencies in antiviral activity have long been associated with enhanced frequency and severity of disease. Two antiviral proteins--Interferon Regulatory Factor 3 (IRF3) and Nuclear Factor Kappa B (NF-κB)--are observed to have document- ed effects on HSV-1 viral replication, neuronal disease, and host mortality. Their importance, while broadly identified, has not been clearly defined in regard to their specific antiviral roles during HSV-1 infections. Our preliminary data suggests that both IRF3 and NF-κB play different, yet significant, roles in the management of neuronal HSV-1 infections. We observed that inhibition of IRF3 led to enhanced neuronal replication and spread in a published model of neuronal HSV-1 infection. In a model of silent HSV-1 infection, we saw that inhibiting NF-κB prevented establishment of silent infections and also promoted their reactivation. These results have led us to hypothesize that IRF3 and NF-κB impact neuronal HSV-1 infection by affecting neuronal trans- mission and genome silencing, respectively. To test our hypothesis, we will experimentally alter the activity of these molecules to observe their effects on neuronal infection. The effect of IRF3 on neuronal transmission will be assessed in Aim 1 by measuring neuronal replication, spread, and the rate of virion transport down axons. In Aim 2, we will further explore the effects of NF-κB activity on silencing, as well as compare how reactivation mediated by NF-κB inhibition compares to other known reactivators of silent HSV-1 infection. These experiments will contribute to a currently lacking understanding of how neuronal HSV-1 infections are controlled. Our results will serve as a foundation for further exploration regarding how IRF3 and NF-κB mediate their effects on transmission and latency, respectively. The increased understanding of these factors will pave the way for more effective management of HSV-1 disease through enhanced antiviral responses.

抗病毒反应在神经元HSV-1感染的管理中起关键作用。抗病毒活性的缺陷长期以来一直与疾病的频率和严重程度增强有关。观察到两种抗病毒蛋白 - 间菌素调节因子3（IRF3）和核因子KAPPA B（NF-κB）对HSV-1病毒复制，神经元疾病和宿主死亡率具有文档-ED影响。它们的重要性虽然广泛确定，但在HSV-1感染期间的特定抗病毒作用方面尚未明确定义。我们的初步数据表明，IRF3和NF-κB在神经元HSV-1感染的管理中扮演着不同但重要的作用。我们观察到，抑制IRF3导致神经元复制增强并在已发表的神经元HSV-1感染模型中传播。在沉默的HSV-1感染模型中，我们看到抑制NF-κB阻止了建立无声感染并促进了它们的重新激活。这些结果使我们假设IRF3和NF-κB分别通过影响神经元传播和基因组沉默来影响神经元HSV-1感染。为了检验我们的假设，我们将在实验上改变这些分子的活性，以观察它们对神经元感染的影响。 IRF3对神经元传输的影响将通过测量神经元复制，扩散和病毒向下轴突传输速率来评估AIM 1。在AIM 2中，我们将进一步探讨NF-κB活性对沉默的影响，并比较NF-κB抑制作用介导的重新激活与静音HSV-1感染的其他已知反抗器相比。这些实验将导致当前缺乏了解神经元HSV-1感染的控制。我们的结果将成为进一步探索IRF3和NF-κB分别对传播和潜伏期的影响的基础。对这些因素的理解增加将为您通过增强的抗病毒反应而更有效地治疗HSV-1疾病铺平道路。