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

对 HSV-1 和 HSV-2 生殖器感染的独特先天免疫反应决定了神经元感染的程度。

基本信息

批准号：
10387788
负责人：
Aisha Grace Lee
金额：
$ 3.27万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10387788
关键词：
Address Adult Affect Afferent Neurons American Automobile Driving Autophagocytosis Autophagosome Biological Assay CCL2 gene CD94 Antigen Cell Death Cells Chemotactic Factors Chronic Disease Communicable Diseases Communication Confocal Microscopy Data Development Disease Disease Outbreaks Disease Outcome Distant Epithelial Cells Female Frequencies Future Genital Genitalia Goals Herpesvirus 1 Human Human Herpesvirus 2 IFNAR1 gene Image Immune Immune response In Vitro Infection Infection Control Infiltration Inflammatory Innate Immune Response Interferon Type II Interferons Interleukin-18 Investigation Kinetics Knockout Mice Knowledge Lesion Link Mediating Mentorship Methods Modeling Morbidity - disease rate Mucosal Immune Responses Mucous Membrane Mus NK Cell Activation Natural Killer Cells Neurons Nonlytic Outcome Pain Pathway interactions Patients Peripheral Nervous System Physicians Population Production Property Recurrence Reporter Research Research Personnel Resistance to infection Risk Role Scientist Sexually Transmitted Diseases Signal Transduction Simplexvirus Source Symptoms Testing Training Up-Regulation Vaccine Design Vaccines Vagina Viral Viral reservoir Virus Virus Latency Western Blotting adaptive immune response career chemokine disorder risk experience experimental study follow-up genital herpes genital infection high risk improved in vivo innate immune mechanisms interleukin-18 receptor monocyte mouse model neuronal cell body neuroprotection neutralizing antibody novel pathogen receptor recruit response skills transmission process trend vaginal infection

项目摘要

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.

项目概要/摘要生殖器疱疹（GH）是一种常见的性传播感染，发病率很高，并且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 的患者会出现明显的 GH。先前的研究表明，与 HSV-1 GH 患者相比，疾病复发和传播的频率更高。周围神经系统（PNS）中潜伏病毒库重新激活的频率 HSV-2 生殖器感染后相对于 HSV-1 而言始终较大，但尚不清楚这些是否存在。不同的结果是由于病毒的内在特性或宿主反应造成的。为了探索后者，我们的实验室。利用 HSV-1 和 HSV-2 阴道感染的小鼠模型的直接比较，我们确定了这些模型。相对于 HSV-2，HSV-1 诱导加速的适应性免疫反应，更好地保护 PNS 病毒入侵的增加与 NK 细胞依赖性 IFNg 的早期爆发有关。 HSV-1 感染后一天在阴道分泌，但 HSV-2 不分泌，但上游信号驱动。每个模型之间 NK 激活的差异动力学以及下游机制赋予增加的神经对感染的抵抗力都是未知的，这个提议的中心假设是HSV-。 1 局部免疫细胞比 HSV-2 更快地感知生殖器感染，导致粘膜快速分泌 IFNγ 先前的研究已经确定了直接增强神经对感染的抵抗力的关键作用。炎症单核细胞 IL-18 在 HSV-2 感染期间激活 NK 细胞产生 IFNg 的作用。表明在 HSV-1 感染期间该群体有更快招募的趋势，与早期相关为了跟进，我将比较 HSV 期间炎症单核细胞募集的机制。 1 与 HSV-2 感染的比较，并确定差异调节阴道 NK 细胞募集的不同反应 IFNg 产生（目标 1） IFNg 是其他宿主-病原体反应和自噬中已知的自噬诱导剂。是感觉神经元控制 HSV 感染的主要非裂解机制之一。还通过评估 IFNg 是否可以探索粘膜 NK 细胞和 PNS 之间新的潜在串扰可以在体外和体内增强感觉神经元的自噬通量，作为控制 HSV 感染的机制（目标 2）该提案的长期目标是定义针对 HSV-1 和 HSV-1 的独特先天免疫反应。 HSV-2 生殖器感染作为一种方法来识别成功限制宿主反应的必要特征此类研究对于为未来有效的疫苗设计提供信息非常宝贵。为了实现第一个目标，我将实现第二个目标，即进一步发展我的能力。通过与我的赞助商一起制定的精心设计的培训计划，获得作为独立研究人员的自主权， Haina Shin 博士和共同发起人 Wayne Yokoyama 博士，这将 i) 提高我的研究技能，ii) 加强我的研究技能科学传播能力，以及 iii) 提供指导和专业发展机会实现我的职业目标，成为一名未来的医师科学家和传染病领域的学术研究者。