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) 在激发上皮表面抗病毒免疫力、控制感染方面发挥着关键作用局部没有由更有效的全身性 I 型干扰素 (IFN-αβ) 引发的炎症免疫病理学然而，IFN-λ 对皮肤的影响尚未得到广泛研究。 1 型 (HSV-1) 感染上皮细胞，并在小鼠的感觉神经元中形成终生感染。皮肤感染模型中，我们发现缺乏 IFN-λ 信号传导的多个小鼠系出现了更严重的 HSV-1 与野生型小鼠相比，皮肤损伤然而，疾病的严重程度与皮肤中的病毒载量无关。表明 IFN-λ 在抑制炎症免疫病理学中发挥作用。角质形成细胞和白细胞对于预防严重皮肤病是必需的，并且 Ifnlr1-/- 小鼠与 WT 小鼠相比，HSV-1 皮肤损伤中的中性粒细胞浸润更多。 λ 通过抑制中性粒细胞募集和抑制 HSV-1 感染期间的炎症病理学人类 HSV-1 疾病的最大负担是由于终生潜伏感染的重新激活，而不是新的感染，我们开发了一种简单且易于处理的小鼠模型来诱导重新激活。使用该模型，我们发现来自背根神经节的潜在 HSV-1 会产生复发性 HSV-1 皮肤损伤。与 WT 小鼠和其他黄病毒小鼠相比，Ifnlr1-/- 小鼠会出现更严重的再激活疾病。我们发现，虫媒病毒通过吸血蚊子或蜱载体接种到皮肤中。仅当病毒接种在皮肤中时，才能减少寨卡病毒和冷岳病毒引起的病毒血症，而不是当通过皮下接种绕过皮肤屏障时，已知载体唾液会增强虫媒病毒。发病机制部分是通过招募中性粒细胞来实现的，中性粒细胞是一种关键的 IFN-λ 反应细胞类型。皮肤中的信号传导限制黄病毒传播，并且在媒介喂养的情况下这种效果更大。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群 1B：定义致病性免疫反应。受到皮肤中 IFN-λ 的抑制 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：定义作用。 IFN-λ 特别是在 HSV-1 复发性疾病期间 2B：评估病毒复制和皮肤病变的动力学。使用活体动物发光成像形成。目标 3：确定 IFN-λ 对蚊媒和蜱媒黄病毒 3A 的皮肤特异性作用。定义限制蚊媒黄病毒和蜱媒复制的 IFN-λ 反应细胞类型皮肤中的黄病毒3B：研究载体唾液对皮肤中IFN-λ介导的抗病毒免疫的影响。