Antiviral and immunomodulatory effects of interferon lambda in the skin

干扰素 lambda 在皮肤中的抗病毒和免疫调节作用

基本信息

批准号：
10637499
负责人：
Helen Lazear
金额：
$ 59.47万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-13 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10637499
关键词：
Acute Afferent Neurons Anatomy Animals Antiviral Response Arboviruses Arthropods Bacteria Biological Models Blood Bone Marrow Bypass Chimera organism Culicidae Dendritic Cells Disease Encephalitis Epithelial Cells Epithelium Event Exhibits Flavivirus Flavivirus Infections Focal Infection Genetic Transcription Genital Genitalia Herpes Labialis Herpesviridae Herpesvirus 1 Human Image Immune Immune response Infection Infection Control Infectious Skin Diseases Inflammation Inflammatory Interferon Type I Interferons Invaded Investigation Keratitis Kinetics Knockout Mice Langat virus Lesion Leukocytes Maintenance Mediating Modeling Mus Neurons Neutrophil Activation Neutrophil Infiltration Pathogenesis Pathogenicity Pathology Play Population Production Recurrence Recurrent disease Role Saliva Severities Severity of illness Signal Transduction Simplexvirus Site Skin Spinal Ganglia Surface Viral Viral Load result Viremia Virus Virus Replication Wild Type Mouse Zika Virus acute infection animal imaging antiviral immunity cell type conditional knockout cytokine feeding fungus immunoregulation insight interferon-alpha B keratinocyte latent infection luminescence mosquito-borne mouse model neutrophil novel orofacial pathogen programs protective effect reactivation from latency recurrent infection response skin barrier skin disorder skin lesion subcutaneous tick-borne flavivirus tick-borne virus vector vector tick

项目摘要

ABSTRACT Type III interferons (IFN-λ) play a key role eliciting antiviral immunity at epithelial surfaces, controlling infections locally without the inflammatory immune pathology triggered by the more potent systemic type I IFN (IFN-αβ) response. However, the effects of IFN-λ in the skin have not been extensively investigated. Herpes simplex virus type 1 (HSV-1) infects epithelial cells and establishes a life-long infection in sensory neurons. Using a mouse skin infection model, we found that multiple lines of mice lacking IFN-λ signaling developed more severe HSV-1 skin lesions compared to wild-type mice. However, disease severity was uncoupled from viral loads in the skin, suggesting a role for IFN-λ in suppressing inflammatory immune pathology. We found that IFN-λ signaling in both keratinocytes and leukocytes was necessary for protection from severe skin disease and that Ifnlr1-/- mice exhibited greater neutrophil infiltration into HSV-1 skin lesions compared to WT mice. We hypothesize that IFN- λ protects against inflammatory pathology during HSV-1 infection by suppressing neutrophil recruitment and activation. The greatest burden of HSV-1 disease in humans results from reactivation of lifelong latent infections, rather than new infections. We have developed a simple and tractable mouse model to induce reactivation of latent HSV-1 from dorsal root ganglia which produces recurrent HSV-1 skin lesions. Using this model, we found that Ifnlr1-/- mice develop more severe reactivation disease compared to WT mice. Flaviviruses and other arboviruses are inoculated into the skin by blood-feeding mosquito or tick vectors. We found that IFN-λ signaling reduced viremia caused by Zika virus and Langat virus only when the viruses were inoculated in the skin, not when the skin barrier was bypassed by subcutaneous inoculation. Vector saliva is known to enhance arbovirus pathogenesis in part by recruiting neutrophils, a key IFN-λ responsive cell type. We hypothesize that IFN-λ signaling in the skin restricts flavivirus dissemination and that this effect is greater in the context of vector feeding. Aim 1: Define the mechanism by which IFN-λ restricts acute HSV-1 skin disease. 1A: define the IFN-λ responsive leukocyte populations that limit skin lesion severity. 1B: define the pathogenic immune responses suppressed by IFN-λ in the skin. 1C: investigate how IFN-λ signaling in keratinocytes limits HSV-1 skin disease. Aim 2: Define the mechanism by which IFN-λ restricts recurrent HSV-1 skin disease. 2A: define the role of IFN-λ specifically during HSV-1 recurrent disease. 2B: assess the kinetics of viral replication and skin lesion formation using live animal luminescence imaging. Aim 3: Define skin-specific effects of IFN-λ against mosquito-borne and tick-borne flaviviruses. 3A: define the IFN-λ responsive cell types that restrict replication of mosquito-borne flaviviruses and tick-borne flaviviruses in the skin. 3B: investigate the effect of vector saliva on IFN-λ mediated antiviral immunity in the skin.

抽象的 III型干扰素（IFN-λ）在上皮表面引起抗病毒免疫史的关键作用，控制感染局部没有炎症性免疫病理学，由IFN（IFN-αβ）触发的较高的全身性IFN触发回复。但是，IFN-λ在皮肤中的影响尚未得到广泛研究。单纯疱疹病毒 1型（HSV-1）感染上皮细胞，并在感觉神经元中建立终身感染。使用鼠标皮肤感染模型，我们发现缺乏IFN-λ信号传导的多条小鼠会出现更严重的HSV-1 与野生型小鼠相比，皮肤病变。然而，疾病的严重程度与皮肤的病毒负荷没有偶联，提出IFN-λ在抑制炎症性免疫病理学中的作用。我们发现IFN-λ信号在角质形成细胞和白细胞都是防止严重皮肤疾病所必需的，并且IFNLR1 - / - 小鼠与WT小鼠相比，与HSV-1皮肤病变相比，中性粒细胞浸润更大。我们假设IFN- λ通过抑制中性粒细胞募集和激活。人类HSV-1疾病中最大的伯宁是由终身潜在感染重新激活的，而不是新的感染。我们已经开发了一种简单且可拖动的小鼠模型，以引起重新激活从背根神经节产生复发性HSV-1皮肤病变的潜在HSV-1。使用此模型，我们发现与WT小鼠相比，IFNLR1 - / - 小鼠会出现更严重的重新激活疾病。黄病毒和其他通过喂食蚊子或tick媒介，将arbovirus接种到皮肤中。我们发现IFN-λ信号传导仅当在皮肤中接种病毒时，由寨卡病毒和兰加特病毒引起的病毒血症降低，而不是当皮下接种绕过皮肤屏障时。众所周知，载体唾液可以增强arbovirus 发病机理部分通过募集中性粒细胞，这是一种关键的IFN-λ反应性细胞类型。我们假设IFN-λ 皮肤中的信号传导限制了黄病毒的传播，并且在矢量进食的背景下，这种效果更大。目标1：定义IFN-λ限制急性HSV-1皮肤病的机制。 1A：定义IFN-λ 限制皮肤病变严重程度的反应性白细胞种群。 1B：定义致病性免疫反应被皮肤中的IFN-λ抑制。 1C：研究角质形成细胞中的IFN-λ信号如何限制HSV-1皮肤病。目标2：定义IFN-λ限制复发性HSV-1皮肤病的机制。 2a：定义角色在HSV-1复发性疾病期间特别是IFN-λ的。 2B：评估病毒复制和皮肤病变的动力学使用活动物发光成像形成。 AIM 3：定义IFN-λ对蚊子传播和tick传播黄病毒的皮肤特异性作用。 3a：定义IFN-λ响应式细胞类型，这些类型限制了蚊子传播黄病毒和tick传播的复制皮肤中的黄病毒。 3B：研究载体唾液对皮肤中IFN-λ介导的抗病毒免疫的影响。