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

项目摘要/摘要 生殖器疱疹(GH)是一种常见的性传播感染，发病率很高，目前还没有疫苗或治愈方法。 它是由单纯疱疹病毒1型(HSV-1)或HSV-2引起的。有HSV-2生殖器疱疹经历的患者显著 疾病复发和传播的频率高于单纯疱疹病毒1型生长激素患者。之前的研究链接 周围神经系统(PNS)中潜伏病毒库的重新激活频率 在HSV-2生殖器感染后，相对于HSV-1，持续更大。然而，目前还不清楚这些是否 不同的结果是由于固有的病毒特性或宿主反应。为了探索后者，我们的实验室 利用直接比较HSV-1和HSV-2阴道感染的小鼠模型。从这些数据中，我们发现 HSV-1诱导相对于HSV-2的加速适应性免疫反应，更好地保护PNS免受 病毒入侵。增强神经保护与早期爆发依赖NK细胞的IFNG有关 HSV-1感染后一天在阴道内分泌，而HSV-2感染后不分泌。然而，上游信号驱动着 不同模型间NK激活的差异动力学及其下游机制 神经元对感染抵抗力的增强都是未知的。这一提议的中心假设是HSV- 局部免疫细胞对生殖器感染的感知速度比单纯疱疹病毒2型更快，从而导致黏膜快速分泌干扰素γ。 这直接增强了神经元对感染的抵抗力。以前的研究已经确定了一个关键的作用 炎性单核细胞IL-18在单纯疱疹病毒2型感染中激活NK细胞产生干扰素的作用初步数据 表明在HSV-1感染期间，这一群体有更快招募的趋势，与较早的 IFNG生产。作为后续，我将比较单纯疱疹病毒感染过程中炎性单核细胞募集的机制。 1vsHSV-2感染，并确定不同的反应，以不同的方式调节阴道NK细胞募集 IFNG生产(目标1)。IFNG是已知的在其他宿主-病原体反应中自噬的诱导者，以及自噬 是感觉神经元控制HSV感染的主要非溶解机制之一。因此，我会 此外，通过评估IFNG是否有可能在粘膜NK细胞和三叉神经节之间产生新的潜在串扰 可增强体内外感觉神经元的自噬通量作为控制HSV感染的机制 (目标2)。这项建议的长期目标是确定针对HSV-1与 HSV-2生殖器感染作为一种识别成功限制宿主反应的必要特征的方法 神经侵袭。这样的研究对于为未来有效的疫苗设计提供信息将是无价的 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 自主作为一名独立研究人员，通过与我的赞助人一起制定的精心设计的培训计划， Haina Shin博士和共同赞助人Wayne Yokyama博士，这将一)提高我的研究技能，二)加强我的 科学交流能力，以及iii)提供指导和职业发展机会 实现我的职业目标，成为一名未来的传染病内科科学家和学术研究者。

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.