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

局部病毒感染对皮肤伤口愈合的影响：病毒诱导的III型干扰素的影响

• 批准号: 10217681
• 负责人: Christopher C Norbury
• 金额: $ 17.84万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-17 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217681
• 关键词: Ablation; Agonist; Antiviral Agents; Antiviral Response; Area; Bacterial Infections; Blood - brain barrier anatomy; Cell Cycle Regulation; Cells; Complement; Connective Tissue; Cutaneous; Data; Environment; Exposure to; Family; Fibroblasts; Future; Growth; Herpesviridae; Human body; Immune; Immune response; Individual; Infection; Infection prevention; Infectious Skin Diseases; Infiltration; Interferon Receptor; Interferon Type I; Interferon-alpha; Interferons; Knowledge; Lung; Maintenance; Mediating; Methodology; Modeling; Molecular; Nature; Organ; Papillomavirus; Pathogenicity; Pathway interactions; Population; Poxviridae; Prevalence; Process; Production; Receptor Signaling; Regenerative response; Rest; Role; Skin; Skin wound healing; Somatic Cell; Sterility; Surface; System; Testing; Tissues; Tumor-infiltrating immune cells; Viral; Virus; Virus Diseases; Virus Replication; Work; base; commensal bacteria; cytokine; healing; keratinocyte; novel; pathogen; pathogenic bacteria; pathogenic virus; prevent; receptor; recruit; response; side effect; skin barrier; skin wound; therapeutic target; tissue regeneration; tissue repair; wound; wound closure; wound healing

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.

概括 皮肤的表面积约为1.8m2，是人体最大的器官之一，是最大的器官之一，是最大的器官 暴露于环境。维护皮肤屏障对于防止感染的至关重要 共生或致病细菌或其他病原体。但是，研究伤口愈合的机制 主要是在无菌伤害的背景下进行的，从未在上下文中进行 皮肤病毒感染是该提案的重点。大量病毒病原体，例如 乳头瘤病毒，一些疱疹病毒和一些痘病毒，皮肤感染，并导致感染 全球数亿人。这些病毒感染通常会诱导强烈的局部免疫 反应与通常在无菌伤口期间诱导的反应不同。组织范式 更新的是，只有在致病感染清除后，伤口愈合才开始。但是，我们的 初步数据表明，在皮肤病毒复制峰值之前，伤口愈合反应开始。 因此，旨在清除病毒的抗病毒反应可能同时增强和反对个体 高度调节的伤口愈合过程的组成部分正在同时发生。我们的初步数据 表明皮肤病毒感染后的伤口愈合，这对于预防继发细菌至关重要 感染，对无菌伤害显示许多至关重要的差异。这些差异包括 细胞反应的组成以及抗病毒分子（例如干扰素）对伤口的作用 康复。在特定目标1中，我们将建立一个新系统，直接和系统地检查 分子和细胞伤口愈合反应的局部病毒感染。这样我们将确定关键 抗病毒反应的调节剂也影响皮肤愈合。在特定目标2中，我们将建立一个 通过研究III型干扰素（T3-IFN）的作用来测试这些关键调节剂的管道，我们 初步数据表明，仅在病毒感染时强烈诱导，作为伤口的候选调节剂 在我们的管道中康复。有效的伤口愈合需要T3-IFN，但不能控制病毒复制。 T3- IFN是主要在壁垒表面（例如肠道，肺和血液和血液）上产生的细胞因子家族 障碍。 T3-IFN可以独立于病毒生长的控制，包括 控制细胞周期以及募集和调节先天和适应性免疫的激活 细胞。 T3-IFN生产的局部性质使它们成为有前途的治疗目标，因为它们可以是 管理或其动作调制，无需考虑系统性副作用。我们将检查 先前鉴定的T3-IFN诱导的分子的作用，并确定其他T3-IFN调节的调节剂 皮肤伤口愈合。然后，我们将准备扩大我们的研究，以进一步了解T3- IFN调节分子水平的伤口愈合，但也调节其他分子和细胞的作用 在未来的RO1提案中，在伤口愈合反应中，皮肤病毒感染引起的种群。