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.

项目总结/摘要 皮肤是一个复杂的物理和免疫上皮屏障，负责保护宿主 包括病毒病原体在内的外部威胁。专门的免疫因子-包括皮肤特异性免疫 细胞和细胞因子-帮助调节平衡的皮肤免疫反应，防止病原体入侵， 保持屏障完整性。III型干扰素（IFN-λ）是一类抗病毒细胞因子， 其特征在于在上皮屏障处介导这种平衡的抗病毒免疫应答;然而，它们在 皮肤没有被很好地表征。单纯疱疹病毒1型（HSV-1）可以感染皮肤，随后 会导致终生的持续性感染HSV-1感染超过一半的美国成年人， 主要表现为口面部病变，但也引起角膜炎、失明和脑炎。我们将研究 IFN-λ-介导的皮肤中针对急性和复发性HSV-1皮肤感染的免疫。 我们发现，缺乏IFN-λ受体（Ifnlr 1-/-）的小鼠发生更严重的急性皮肤病 与WT小鼠相比，与对病毒复制的直接影响无关， 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生成素（TSLP）的产生，TSLP是调节性T细胞的已知启动子， （Treg）功能。在目的1中，我将检验我的假设，即IFN-λ诱导角质形成细胞产生TSLP， 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。我会 评估IFN-λ-角质形成细胞-Treg信号传导轴在保护免受急性HSV-1皮肤病理中的作用， 鉴定角质形成细胞中由IFN-λ信号传导调节的皮肤免疫群体，并定义IFN-λ依赖性 在原代鼠角质形成细胞中的转录应答。 我们还发现，Ifnlr 1-/-小鼠表现出延迟的病毒清除，并出现更严重的复发性 与WT小鼠相比，HSV-1皮肤病变表明IFN-λ信号在促进适应性免疫中的作用 皮肤的反应。在目标2中，我将检验我的假设，即IFN-λ通过DC信号促进生成 HSV-1特异性的皮肤驻留记忆CD 8 + T细胞，其限制HSV-1传播和病毒诱导 复发性HSV-1皮肤病期间的炎症。我将确定IFN-λ信号是如何在 白细胞影响重新激活的HSV-1在整个皮肤节的定位，皮肤免疫病理学， HSV-1反复感染时皮肤驻留和浸润免疫谱 我提议的项目将研究皮肤中的病毒免疫学，我们的发现可以用于 开发针对病毒和免疫介导的皮肤病变的疗法。我提出的训练计划， 来自海伦·拉泽尔博士和杰森·惠特迈尔博士的研究将给我提供病毒学和免疫学方面的研究经验 同时发展我的教学、指导、领导和项目管理技能。我的训练计划将 准备让我成为一名学术教授，领导一个研究病毒与宿主相互作用的研究项目。