Distinct innate immune responses to HSV-1 versus HSV-2 genital infection determine extent of neuronal infection.

项目总结/摘要 生殖器疱疹（GH）是一种常见的性传播感染，发病率很高，没有疫苗或治愈方法。 它是由单纯疱疹病毒-1（HSV-1）或HSV-2引起的。患有HSV-2 GH的患者 与HSV-1 GH患者相比，疾病复发和传播的频率更高。以前的研究与 周围神经系统（PNS）中潜伏病毒库的再激活频率 HSV-2生殖器感染后相对于HSV-1持续更大。然而，目前尚不清楚这些 不同的结果是由于内在的病毒特性或宿主反应。为了探索后者，我们的实验室 利用HSV-1和HSV-2阴道感染的鼠模型的直接比较。从这些，我们发现 HSV-1相对于HSV-2诱导加速的适应性免疫应答， 病毒入侵神经保护作用的增强与NK细胞依赖性IFNg的早期爆发有关， HSV-1感染后1天分泌于阴道，但HSV-2感染后1天不分泌。然而，上游信号驱动 每个模型之间NK活化的差异动力学以及下游机制赋予 增加的神经元对感染的抵抗力都是未知的。该建议的核心假设是HSV- 1生殖器感染比HSV-2更快地被局部免疫细胞感知，导致IFNγ的快速粘膜分泌 直接增强神经元对感染的抵抗力。以前的研究已经确定了一个关键作用， 炎性单核细胞IL-18在HSV-2感染期间活化NK细胞产生IFNg中的作用。初步数据 提示在HSV-1感染期间，该人群有更快招募的趋势，与早期感染相关。 IFNg生产。为了进一步研究，我将比较HSV-1感染过程中炎症单核细胞募集的机制。 1与HSV-2感染，并确定差异调节阴道NK细胞募集的不同反应 IFNg生产（目标1）。IFNg是其他宿主-病原体应答中的自噬的已知诱导剂，并且自噬 是感觉神经元控制HSV感染的主要非溶解机制之一。所以我会 还通过评估IFNg是否 在体外和体内可以增加感觉神经元中的自噬通量，作为控制HSV感染的机制 (Aim 2）。这项建议的长期目标是确定不同的先天免疫反应，HSV-1与 HSV-2生殖器感染作为一种方法，以确定宿主反应的必要特征，成功限制 神经元浸润这样的研究对于为未来有效的疫苗设计提供信息将是非常宝贵的 对抗这两种病毒为了实现第一个目标，我将实现我的第二个目标，即进一步发展我的 作为一个独立的研究人员，通过与我的赞助商精心制定的培训计划， 博士Haina Shin和共同赞助人韦恩横山博士，这将i）提高我的研究技能，ii）加强我的研究能力， 科学交流能力，以及iii）提供导师和专业发展机会， 实现我的职业目标，成为一个未来的医生，科学家和传染病的学术研究者。

PROJECT SUMMARY/ABSTRACT Genital herpes (GH) is a common sexually transmitted infection with significant morbidity and no vaccine or cure. It is caused by Herpes Simplex Virus-1 (HSV-1) or HSV-2. Patients who have HSV-2 GH experience significantly higher frequency of disease recurrence and transmission than patients with HSV-1 GH. Previous studies linked frequency of reactivation to reservoirs of latent virus in the peripheral nervous system (PNS) that were consistently larger after HSV-2 genital infection relative to HSV-1. However, it was unknown whether these disparate outcomes were due to intrinsic viral properties or the host response. To explore the latter, our lab utilizes direct comparisons of murine models of HSV-1 and HSV-2 vaginal infection. From these, we identified that HSV-1 induces an accelerated adaptive immune response relative to HSV-2, better protecting the PNS from viral invasion. Increased neuroprotection was linked to an early burst of NK cell dependent IFNg that was secreted in the vagina one day after HSV-1 but not HSV-2 infection. However, the upstream signals driving differential kinetics of NK activation between each model as well as the downstream mechanisms conferring increased neuronal resistance to infection are both unknown. The central hypothesis of this proposal is that HSV- 1 genital infection is sensed by local immune cells faster than HSV-2, leading to rapid mucosal secretion of IFNγ that directly enhances neuronal resistance to infection. Previous studies have identified a key role for inflammatory monocyte IL-18 in activating NK cells to produce IFNg during HSV-2 infection. Preliminary data suggests a trend towards faster recruitment of this population during HSV-1 infection, correlating with earlier IFNg production. To follow up, I will compare the mechanism of inflammatory monocyte recruitment during HSV- 1 vs HSV-2 infection and identify the distinct responses that differentially regulate vaginal NK cell recruitment IFNg production (Aim 1). IFNg is a known inducer of autophagy in other host-pathogen responses, and autophagy is one of the primary non-lytic mechanisms by which sensory neurons control HSV infection. Therefore, I will also explore the novel potential crosstalk between mucosal NK cells and the PNS by evaluating whether IFNg can augment autophagic flux in sensory neurons in vitro and in vivo as a mechanism to control HSV infection (Aim 2). The long-term objective of this proposal is to define the distinct innate immune responses to HSV-1 vs HSV-2 genital infection as a method to identify the requisite features of a host response that successfully limits neuronal invasion. Such investigation would be invaluable for informing future vaccine design that is effective against both viruses. In pursuit of this first objective, I will achieve my second objective of further developing my autonomy as an independent researcher through a carefully crafted training plan developed with my sponsor, Dr. Haina Shin, and co-sponsor, Dr. Wayne Yokoyama, that will i) enhance my research skills, ii) strengthen my abilities in scientific communication, and iii) provide mentorship and professional development opportunities to achieve my career goals to be a future physician-scientist and academic investigator in infectious disease.