Temporal Functions of Interferon Lambda Signaling During Acute and Recurrent Herpes Simplex Virus Type 1 Skin Infection

急性和复发性单纯疱疹病毒 1 型皮肤感染期间干扰素 Lambda 信号传导的时间功能

• 批准号: 10536270
• 负责人: Drake Thomas Philip
• 金额: $ 3.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536270
• 关键词: Acute; Acute Disease; Adult; Affect; Afferent Neurons; Antigen-Antibody Complex; Automobile Driving; Blindness; CD8-Positive T-Lymphocytes; Cells; Complex; Dendritic Cells; Disease; Educational process of instructing; Encephalitis; Environment; Epithelial; Epithelial Cells; Equilibrium; Exhibits; Flow Cytometry; Foundations; Frequencies; Future; Gastrointestinal tract structure; Gene Expression Profile; Generations; Genetic Transcription; Herpesvirus 1; Home; Immune; Immune response; Immunity; Immunohistochemistry; Immunologic Factors; Immunologics; Immunology; Infection; Infectious Skin Diseases; Inflammation; Inflammatory; Interferon-alpha; Interferons; Invaded; Keratitis; Leadership; Lesion; Leukocytes; Life; Luciferases; Mediating; Memory; Mentors; Mus; Pathologic; Pathology; Phenotype; Population; Production; Recurrence; Recurrent disease; Regulatory T-Lymphocyte; Research; Respiratory System; Role; Sensory; Signal Transduction; Skin; T memory cell; T-Lymphocyte; TSLP gene; Testing; Training; Tumor-infiltrating immune cells; Viral; Virus; Virus Replication; adaptive immune response; adaptive immunity; antiviral immunity; cell type; chronic infection; cytokine; dermatome; draining lymph node; experience; immunopathology; immunoregulation; insight; interest; keratinocyte; luminescence; lymph nodes; mRNA sequencing; migration; mouse model; neutralizing antibody; neutrophil; orofacial; pathogen; pathogenic virus; prevent; professor; programs; promoter; receptor; recruit; response; skills; skin disorder; skin lesion; therapy development; virology; virus host interaction

PROJECT SUMMARY/ABSTRACT The skin is a complex physical and immunologic epithelial barrier responsible for protecting the host from external threats, including viral pathogens. Specialized immune factors—including skin-specific immune cells and cytokines—help mediate a balanced skin immune response that prevents pathogen invasion while maintaining barrier integrity. Type III interferons (IFN-λ) are a class of antiviral cytokines that have been characterized to mediate this balanced, antiviral immune response at epithelial barriers; however, their role in the skin is not well-characterized. Herpes simplex virus type 1 (HSV-1) can infect the skin, and subsequently sensory neurons where it causes a lifelong, persistent infection. HSV-1 infects more than half of US adults and primarily manifests as orofacial lesions, but also causes keratitis, blindness, and encephalitis. We will examine IFN-λ-mediated immunity in the skin against acute and recurrent HSV-1 skin infection. We found that mice lacking the IFN-λ receptor (Ifnlr1-/-) developed more severe acute skin disease compared to WT mice, independent of a direct effect on viral replication, and that loss of IFN-λ signaling in keratinocytes recapitulated this phenotype. We found also found that treating keratinocytes with IFN-λ induced the production of the cytokine thymic stromal lymphopoietin (TSLP), a known promoter of regulatory T cell (Treg) functions. In Aim 1, I will test my hypothesis that IFN-λ-induced TSLP production by keratinocytes promotes regulatory T cell (Treg) function and restricts inflammatory pathology during acute disease. I will evaluate the role of an IFN-λ-keratinocyte-Treg signaling axis in protecting from acute HSV-1 skin pathology, identify skin immune populations modulated by IFN-λ signaling in keratinocytes, and define IFN-λ-dependent transcriptional responses in primary murine keratinocytes. We also found that Ifnlr1-/- mice exhibited delayed viral clearance and developed more severe recurrent HSV-1 skin lesions compared to WT mice, suggesting a role for IFN-λ signaling in promoting adaptive immune responses in the skin. In Aim 2, I will test my hypothesis that IFN-λ signals through DCs to promote generation of HSV-1-specific, skin-resident memory CD8+ T cells that restrict HSV-1 spread and virus-induced inflammation during recurrent HSV-1 skin disease. I will determine how of IFN-λ signaling specifically in leukocytes affects localization of reactivated HSV-1 throughout the dermatome, skin immunopathology, and the skin-resident and infiltrating immune profiles during recurrent HSV-1 infection My proposed project will investigate viral immunology in the skin and our findings can be used to develop therapies for viral- and immune-mediated skin pathologies. My proposed training plan, under guidance from Dr. Helen Lazear and Dr. Jason Whitmire, will give me research experience in virology and immunology while developing my teaching, mentoring, leadership, and project management skills. My training plan will prepare me to become an academic professor leading a research program investigating virus-host interactions.

项目摘要/摘要 皮肤是一个复杂的物理和免疫学上皮屏障，负责保护宿主 来自外部威胁，包括病毒病原体。专门的免疫因素 - 包括皮肤特异性免疫因素 细胞和细胞因子 - 螺旋介导平衡的皮肤免疫反应，以防止病原体侵袭，而 保持障碍完整性。 III型干扰素（IFN-λ）是一类抗病毒细胞因子 旨在调节上皮屏障的这种平衡的抗病毒免疫反应；但是，它们在 皮肤没有很好的特征。单纯疱疹病毒1型（HSV-1）可以感染皮肤，然后感染皮肤 感官神经元会引起终生的持续感染。 HSV-1感染超过一半的美国成年人 原发性表现为口面病变，但也会引起角膜炎，失明和脑炎。我们将检查 IFN-λ介导的皮肤免疫力可针对急性和复发性HSV-1皮肤感染。 我们发现缺乏IFN-λ受体（IFNLR1 - / - ）的小鼠出现了更严重的急性皮肤病 与WT小鼠相比，与直接对病毒复制的直接影响以及IFN-λ信号的损失无关 角质形成细胞概括了这种表型。我们还发现，用IFN-λ处理角质形成细胞 细胞因子胸腺基质淋巴细胞素（TSLP）的产生，这是已知的调节T细胞的启动子 （Treg）功能。在AIM 1中，我将测试我的假设，即IFN-λ诱导的TSLP由角质形成细胞产生 促进调节性T细胞（TREG）功能，并限制急性疾病期间的炎症病理学。我会 评估IFN-λ-KERATINOCYTE-Treg信号传导轴在保护急性HSV-1皮肤病理学中的作用， 识别由IFN-λ信号在角质形成细胞中调节的皮肤免疫吞噬，并定义IFN-λ依赖性 原代鼠角质形成细胞中的转录反应。 我们还发现IFNLR1 - / - 小鼠暴露了延迟病毒清除率，并形成更严重的复发 与WT小鼠相比，HSV-1皮肤病变 皮肤的反应。在AIM 2中，我将测试我的假设，即IFN-λ通过DC信号促进产生 HSV-1特异性的皮肤记忆CD8+ T细胞，限制HSV-1扩散并诱导病毒诱导 复发性HSV-1皮肤病期间的炎症。我将在 白细胞会影响整个皮肤病，皮肤免疫病理学和 复发性HSV-1感染期间的皮肤居民和浸润的免疫特征 我提出的项目将研究皮肤中的病毒免疫学，我们的发现可用于 开发用于病毒和免疫介导的皮肤病理的疗法。我提出的培训计划，在指导下 来自Helen Lazear博士和Jason Whitmire博士，将为我提供病毒学和免疫学研究经验 在发展我的教学，心理，领导和项目管理技能的同时。我的培训计划将 我准备成为一名学术教授，领导一项研究研究病毒 - 宿主相互作用的研究计划。