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：
10540737
负责人：
Aisha Grace Lee
金额：
$ 5.22万
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/10540737
关键词：
Acceleration 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 IL18 gene Image Immune Immune response In Vitro Infection Infection Control Infiltration Inflammatory Innate Immune Response Interferon Type II Interferons Invaded 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 Pain Pathway interactions Patients Peripheral Nervous System Physicians Population Production Property Recurrence Recurrent disease 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 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 outcome disparities 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.

项目摘要/摘要生殖器疱疹（GH）是一种常见的性传播感染，具有明显的发病率，没有疫苗或治疗。它是由单纯疱疹病毒-1（HSV-1）或HSV-2引起的。具有HSV-2 GH经验的患者与HSV-1 GH患者相比，疾病复发和传播的频率更高。先前的研究链接向周围神经系统（PNS）中潜在病毒储存的重新激活的频率相对于HSV-1，HSV-2生殖器感染后始终更大。但是，尚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引起的。为了探索后者，我们的实验室利用HSV-1和HSV-2阴道感染的鼠模型的直接比较。从中，我们确定了 HSV-1会影响相对于HSV-2的加速适应性免疫响应，更好地保护PNS 病毒入侵。神经保护的增加与早期的NK细胞依赖性ifng有关在HSV-1后的一天，在阴道中分泌，而不是HSV-2感染。但是，上游信号驾驶每个模型之间的NK激活以及下游机制会议的差异动力学会议神经元对感染的耐药性均未知。该提议的中心假设是HSV- 1比HSV-2更快地通过局部免疫细胞感知生殖器感染，从而导致IFNγ的粘膜快速分泌这直接增强了对感染的神经元抗性。先前的研究已经确定了激活NK细胞在HSV-2感染期间激活NK细胞中的炎性单核细胞IL-18。初步数据提出在HSV-1感染期间更快招募该人群的趋势，与早期相关 IFNG生产。为了跟进，我将比较HSV-期间炎症单核细胞募集的机制 1 vs HSV-2感染并确定不同调节阴道NK细胞募集的不同反应 IFNG生产（AIM 1）。 IFNG是其他宿主病原体反应中自噬的已知诱导剂，并且自噬是感觉神经元控制HSV感染的主要非散光机制之一。因此，我会的还通过评估IFNG是否会探索粘膜NK细胞和PN之间的新型潜在串扰可以在体外和体内增强感觉神经元中的自噬通量作为控制HSV感染的机制（目标2）。该提议的长期目标是定义对HSV-1与HSV-1的不同先天免疫反应 HSV-2生殖器感染是确定成功限制宿主反应的必要特征的方法神经元入侵。此类投资对于有效的未来疫苗设计将是无价的反对这两种病毒。为了追求第一个目标，我将实现我的第二个目标，以进一步发展我的通过我的赞助商制定的精心制作的培训计划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，我将提高我的研究技能，ii）加强我的科学沟通的能力，以及iii）提供指导和专业发展的机会实现我的职业目标，成为传染病的未来身体科学家和学术研究者。