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

抗病毒反应在神经元HSV-1感染的治疗中起着关键作用。长期以来，抗病毒活性的不足一直与疾病的频率和严重性增加有关。两种抗病毒蛋白--干扰素调节因子3(IRF3)和核因子KappaB(NF-κB)--对单纯疱疹病毒1型病毒复制、神经元性疾病和宿主死亡率有文献记载的影响。虽然它们的重要性得到了广泛的确认，但关于它们在HSV-1感染期间的具体抗病毒作用还没有明确定义。我们的初步数据表明，IRF3和NF-κB在神经性单纯疱疹病毒感染的管理中发挥着不同但重要的作用。我们观察到，抑制IRF3导致了神经元复制的增强和在已发表的神经元HSV-1感染模型中的传播。在单纯疱疹病毒1型静止性感染的模型中，我们看到抑制NF-κB可以阻止静止性感染的建立，并促进它们的重新激活。这些结果使我们假设IRF3和NF-κB分别通过影响神经元传递和基因组沉默来影响神经元HSV1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，以观察它们对神经元感染的影响。在目标1中，将通过测量神经元的复制、扩散和病毒粒子向轴突下移的速率来评估IRF3对神经元传递的影响。在目标2中，我们将进一步探讨核因子-κB活性对沉默的影响，以及比较核因子-κB抑制介导的再激活与其他已知的静止型单纯疱疹病毒1感染的再激活因子的比较。这些实验将有助于目前对神经元HSV-1感染是如何控制的缺乏了解。我们的结果将为进一步探讨IRF3和NF-κB如何分别调节其对传输和潜伏期的影响奠定基础。对这些因素的更多了解将为通过增强抗病毒反应更有效地管理HSV-1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.