The effect of local virus infection upon cutaneous wound healing: the impact of virus-induced Type III IFNs

摘要 皮肤的表面积约为1.8平方米，是人体最大的器官之一，也是世界上最大的器官之一 暴露在环境中。维护皮肤屏障对于预防感染至关重要。 共生细菌或致病细菌，或其他病原体。然而，伤口愈合机制的研究 主要是在无菌伤害的情况下进行的，从来没有在 皮肤病毒感染的问题，这是这项提案的重点。相当数量的病毒病原体，如 乳头瘤病毒、一些疱疹病毒和一些痘病毒通过皮肤感染并导致感染。 全世界数以亿计的人。这些病毒感染通常可以诱导强烈的局部免疫。 不同于通常在无菌创伤期间引起的反应。组织的范式 溃疡是指伤口只有在病原体感染清除后才开始愈合。然而，我们的 初步数据表明，伤口愈合反应在皮肤病毒复制高峰期之前就开始了。 因此，旨在清除病毒的抗病毒反应可能既增强又反对个体 这是同时发生的高度受监管的伤口愈合过程的组成部分。我们的初步数据 提示皮肤病毒感染后伤口愈合，这是预防继发性细菌的关键 感染，显示了与无菌创伤的一些关键区别。这些差异包括 细胞反应的组成，以及抗病毒分子，如干扰素，对伤口的影响 治愈。在具体目标1中，我们将建立一个新的制度，直接和系统地审查 局部病毒感染对分子和细胞创伤愈合反应的影响。通过这种方式，我们将识别密钥 也影响皮肤愈合的抗病毒反应的调节器。在具体目标2中，我们将建立一个 通过研究III型干扰素(T3-干扰素)的作用来测试这些关键调节因子，我们的 初步数据表明，只有在病毒感染时才会强烈诱导，作为伤口的候选调节因子 我们的治疗正在进行中。T3-干扰素是有效伤口愈合所必需的，但不是控制病毒复制所必需的。T3- 干扰素是一个细胞因子家族，主要在肠道、肺和血脑等屏障表面产生。 障碍。与病毒生长控制无关的T3-IFN可以有大量的下游效应，包括 控制细胞周期以及招募和调节先天免疫和获得性免疫的激活 细胞。T3-干扰素产生的局部性使它们成为一个有希望的治疗靶点。 管理或调整他们的行动，而不需要考虑系统性副作用。我们将研究 先前识别的T3-干扰素诱导分子的作用，以及识别其他的T3-干扰素调节因子 皮肤伤口愈合的可能性。然后，我们将准备扩大我们的研究，以进一步了解T3- 干扰素在分子水平上调节伤口愈合，也是为了研究其他分子和细胞的作用 在未来的RO1建议中，皮肤病毒感染诱导的人群在伤口愈合反应中的作用。

SUMMARY The skin, with its surface area of approx 1.8m2, is one of the largest organs in the human body and is the most exposed to the environment. Maintenance of the skin barrier is of paramount importance to prevent infection by commensal or pathogenic bacteria, or other pathogens. However, study of the mechanisms of wound healing has been conducted primarily in the context of sterile wounding, and has never been conducted in the context of cutaneous virus infection, the focus of this proposal. A significant number of viral pathogens, such as papillomaviruses, some herpesviruses and some poxviruses, infect cutaneously and are responsible for infection of hundreds of millions of people worldwide. These viral infections can often induce a strong local immune response that differs from the response that is normally induced during sterile wounding. The paradigm of tissue renegeration is that wound healing only begins after clearance of a pathogenic infection. However, our preliminary data indicates that a wound healing response begins prior to the peak of cutaneous virus replication. Therefore, the antiviral response that aims to clear the virus can likely both enhance and oppose individual components of the highly regulated wound healing process that is occurring concurrently. Our preliminary data indicate that wound healing after cutaneous virus infection, which is crucial to prevent secondary bacterial infections, displays a number of crucial differences to sterile wounding. These differences include the composition of the cellular response, and the effects of antiviral molecules, such as interferons, upon wound healing. In Specific Aim 1 we will establish a new system to directly and systematically examine the effects of the local virus infection upon the molecular and cellular wound healing response. In this way we will identify key regulators of the antiviral response that also impact cutaneous healing. In Specific Aim 2 we will establish a pipeline to test these key regulators by investigating the role of Type III interferons (T3-IFN), which our preliminary data indicate are strongly induced only upon virus infection, as a candidate regulator of wound healing in our pipeline. T3-IFN are required for effective wound healing, but not control of virus replication. T3- IFN are a family of cytokines that are primarily produced at barrier surfaces, such as gut, lung and blood brain barrier. T3-IFNs can have a large number of downstream effects independent of control of virus growth, including control of the cell cycle as well as recruitment and modulation of the activation of innate and adaptive immune cells. The localized nature of T3-IFN production makes them a promising therapeutic target, as they can be administered, or their action modulated, without the need to account for systemic side effects. We will examine the role of previously identified T3-IFN-induced molecules, and identify additional T3-IFN-modulated regulators of cutaneous wound healing. We will then be poised to expand our studies, both to further understand how T3- IFN modulates wound healing at the molecular level, but also to investigate the role of other molecules and cell populations induced by cutaneous virus infection in the wound healing response, in a future RO1 proposal.