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

抗病毒反应在神经元HSV-1感染的管理中起着关键作用。长期以来，抗病毒活性的缺乏与疾病的频率和严重程度增加有关。两种抗病毒蛋白——干扰素调节因子3 （IRF3）和核因子κB （NF-κB）——被观察到对HSV-1病毒复制、神经元疾病和宿主死亡率有文献记载的影响。它们的重要性虽然得到广泛确认，但在1型单纯疱疹病毒感染期间，它们的具体抗病毒作用尚未得到明确界定。我们的初步数据表明，IRF3和NF-κB在神经元型HSV-1感染的管理中发挥着不同但重要的作用。在已发表的神经元型HSV-1感染模型中，我们观察到抑制IRF3导致神经元复制和传播增强。在沉默型HSV-1感染模型中，我们发现抑制NF-κB可以阻止沉默型感染的建立，并促进其再激活。这些结果使我们假设IRF3和NF-κ b分别通过影响神经元传递和基因组沉默来影响神经元HSV-1感染。为了验证我们的假设，我们将通过实验改变这些分子的活性，观察它们对神经元感染的影响。IRF3对神经元传递的影响将在Aim 1中通过测量神经元复制、扩散和病毒粒子沿轴突运输的速率来评估。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抑制介导的再激活与其他已知的沉默型HSV-1感染的再激活相比如何。这些实验将有助于目前缺乏对如何控制神经元型单纯疱疹病毒感染的理解。我们的研究结果将为进一步探索IRF3和NF-κB分别介导其传播和延迟的影响奠定基础。对这些因素的进一步了解将为通过增强抗病毒反应更有效地管理1型单纯疱疹病毒疾病铺平道路。

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.