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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.

项目总结/文摘