Antiviral and immunomodulatory effects of interferon lambda in the skin

摘要 III型干扰素（IFN-λ）在上皮表面引发抗病毒免疫、控制感染中起关键作用 局部无更强效的全身性I型IFN（IFN-αβ）引发的炎症免疫病理 反应然而，IFN-λ在皮肤中的作用尚未得到广泛研究。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 在皮肤感染模型中，我们发现缺乏IFN-λ信号传导的多系小鼠发展为更严重的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， 提示IFN-λ在抑制炎性免疫病理中的作用。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病所必需的， 与WT小鼠相比，表现出更多的中性粒细胞浸润到HSV-1皮肤病变中。我们假设干扰素- λ通过抑制嗜中性粒细胞募集来保护HSV-1感染期间的炎症病理， activation.人类HSV-1疾病的最大负担是由终身潜伏感染的再激活引起的， 而不是新的感染。我们已经开发了一种简单易行的小鼠模型来诱导 来自背根神经节的潜伏性HSV-1，其产生复发性HSV-1皮肤损伤。通过这个模型，我们发现 Ifnlr 1-/-小鼠比WT小鼠发生更严重的再激活疾病。黄病毒和其他 虫媒病毒通过吸血蚊子或蜱虫媒介接种到皮肤中。我们发现IFN-λ信号 只有当病毒接种在皮肤中时，才能减少寨卡病毒和Langat病毒引起的病毒血症， 当皮肤屏障被皮下接种绕过时。已知媒介唾液能增强虫媒病毒 致病机制部分通过募集中性粒细胞（一种关键的IFN-λ应答细胞类型）来实现。我们假设IFN-λ 皮肤中的信号传导限制了黄病毒传播，并且在媒介喂养的情况下这种效果更大。 目的1：明确IFN-λ抑制急性HSV-1皮肤病的机制。1A：定义IFN-λ 反应性白细胞群，限制皮肤病变的严重程度。1B：定义致病性免疫反应 在皮肤中被IFN-λ抑制。图1C：研究角质形成细胞中的IFN-λ信号传导如何限制HSV-1皮肤病。 目的2：明确IFN-λ抑制HSV-1皮肤病复发的机制。2A：定义角色 IFN-λ在HSV-1复发性疾病中的特异性表达。2B：评估病毒复制和皮肤损伤的动力学 形成使用活动物发光成像。 目的3：确定IFN-λ对蚊媒和蜱媒黄病毒的皮肤特异性作用。3A： 定义限制蚊媒黄病毒和蜱媒黄病毒复制的IFN-λ应答细胞类型 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。

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.