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

总结 皮肤的表面积约为1.8平方米，是人体最大的器官之一，也是人体内最重要的器官。 暴露在环境中。维持皮肤屏障对于预防感染是至关重要的， 细菌或致病菌，或其他病原体。然而，对创伤愈合机制的研究 主要是在无菌创伤的情况下进行的，从未在无菌创伤的情况下进行过。 皮肤病毒感染是本提案的重点。大量的病毒病原体，如 乳头状瘤病毒、某些疱疹病毒和某些痘病毒感染尿道，并导致感染 全世界数以亿计的人。这些病毒感染往往可以诱导强烈的局部免疫 与在无菌创伤期间正常诱导的反应不同的反应。组织的范例 另一种说法是伤口愈合仅在病原体感染清除后才开始。但我们的 初步数据表明伤口愈合反应在皮肤病毒复制的高峰之前开始。 因此，旨在清除病毒的抗病毒反应可能既增强又对抗个体 同时发生的高度调节的伤口愈合过程的组成部分。我们的初步数据 表明皮肤病毒感染后伤口愈合，这对于防止继发性细菌感染至关重要 感染，显示了一些关键的差异，以无菌伤口。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系统，直接和系统地检查 局部病毒感染后的分子和细胞伤口愈合反应。这样我们就能找到关键 调节抗病毒反应，也影响皮肤愈合。在具体目标2中，我们将建立 通过研究III型干扰素（T3-IFN）的作用来测试这些关键调节因子， 初步数据表明，作为伤口的候选调节剂， 治愈在我们的管道。T3-IFN是有效伤口愈合所需的，但不是控制病毒复制所需的。T3- IFN是一个细胞因子家族，主要在屏障表面产生，如肠、肺和血脑 屏障T3-IFN可以具有大量的下游效应，而与病毒生长的控制无关，包括 控制细胞周期以及募集和调节先天性和适应性免疫的激活 细胞T3-IFN产生的局部性质使它们成为有希望的治疗靶点，因为它们可以是 这些药物可以被施用或调节其作用，而不需要考虑全身性副作用。我们将研究 先前鉴定的T3-IFN诱导分子的作用，并鉴定额外的T3-IFN调节调节因子 皮肤伤口愈合的过程然后，我们将准备扩大我们的研究，既进一步了解T3- IFN在分子水平上调节伤口愈合，但也要研究其他分子和细胞的作用。 在未来的RO 1提案中，研究了皮肤病毒感染诱导的伤口愈合反应。

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.