Regulation of antiviral immunity at barrier surfaces by interleukin-1 family cytokines

IL-1 家族细胞因子对屏障表面抗病毒免疫的调节

• 批准号: 10056388
• 负责人: Megan Horn Orzalli
• 金额: $ 24.9万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056388
• 关键词: Accreditation; Advisory Committees; Antiviral Agents; Antiviral Response; Award; Biochemical; Cell Communication; Cell Death; Cell model; Cells; Collaborations; Committee Members; Communicable Diseases; Educational workshop; Epithelial Cells; Eye; Family; Family member; Fibroblasts; Gene Expression; Genetic; Genetic Transcription; Goals; Human; IRF1 gene; Immune response; Immunology; In Vitro; Infection; Inflammasome; Inflammatory; Institution; Interferons; Interleukin-1; Interleukin-1 Receptors; Invaded; Link; Lung; Mediating; Mentors; Modeling; Oral cavity; Oral mucous membrane structure; Organoids; Pathway interactions; Phase; Play; Polyubiquitination; Positioning Attribute; Proteins; Receptor Signaling; Regulation; Research; Research Personnel; Role; Route; Signal Pathway; Signal Transduction; Site; Skin; Stimulus; Stratified Epithelium; Surface; Testing; Therapeutic; Tissues; Training; United States National Institutes of Health; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; Virus Replication; antiviral immunity; career; career development; course development; cytokine; experimental study; human model; in vitro Model; insight; keratinocyte; novel strategies; pathogen; prevent; programs; response; skills; tenure track; transcription factor; vaccine development; virology

Project Summary My long-term goal is to obtain a tenure track position at an accredited academic institution where I will perform independent research at the interface between virology and innate immunology. I envision developing a research program that utilizes novel approaches to investigate mechanisms of antiviral immunity at barrier surfaces, such as those of the skin, gut, lung, and oral mucosa. Obtaining the NIH pathway to independence K99/R00 award will provide me with the additional training I need to succeed as an independent investigator. In this proposal, I outline a training plan that encompasses formal coursework, participation in career development courses and workshops, and scientific collaboration with advisory committee members. The skills that I will acquire during the mentored phase of the award will make me uniquely qualified to answer important questions related to the host response to viral infection. The scientific goal of this study is to understand how non-hematopoietic cells contribute to antiviral immunity at barrier surfaces. Barrier surfaces are primary routes of entry for diverse viruses, and the initial antiviral responses elicited at these sites can have marked effects on viral spread within an infected host. Many viruses that infect barrier surfaces initially replicate within epithelial cells. However, the antiviral responses induced by these cells and their roles in preventing viral spread from the primary site of infection are poorly understood. Studies of antiviral immunity in epithelial cells have predominately focused on the role of interferons (IFNs). Yet, many viruses encode proteins that block IFN expression. Therefore, I propose that cells have alternative mechanisms to communicate infection and restrict virus replication during encounters with viruses that block IFN expression. This proposal is founded on my observation that viruses that inhibit IFN expression promote the release of interleukin (IL)-1 cytokines from infected epithelial cells, and that IL-1 cytokines elicit an antiviral state in human fibroblasts. I hypothesize that epithelial cells infected with IFN- evading viruses release preformed IL-1 cytokines to induce an antiviral response in neighboring non- hematopoietic cells. In addition, I propose that local IL-1R signaling in barrier tissues plays an important role in controlling virus spread from the initial site of infection. In this proposal, I will explore key aspects of this model of antiviral immunity.! Specifically, I will determine the genetic and biochemical basis for the mechanism of IL-1 cytokine release from virus-infected epithelial cells (Aim 1), determine the mechanisms by which a critical regulator of IL-1 cytokine induced antiviral responses, the transcription factor IRF1, is activated or inhibited (Aim 2), and define the antiviral mechanism(s) of non-hematopoietic cell IL-1 receptor (IL-1R) signaling in human skin (Aim 3). The results of these studies will provide important insight into the earliest encounters between host and virus, and will ultimately set the framework for my successful career as an independent investigator.

项目摘要 我的长期目标是在一家认可的学术机构获得终身教职，在那里我将 在病毒学和先天免疫学之间进行独立研究。我设想的是发展 利用新方法研究屏障抗病毒免疫机制的研究计划 表面，如皮肤、肠道、肺和口腔粘膜的表面。获得美国国立卫生研究院的独立途径 K99/R00奖将为我提供作为一名独立调查员取得成功所需的额外培训。在……里面 在这项提议中，我概述了一项包含正式课程、参与职业生涯的培训计划 发展课程和讲习班，以及与咨询委员会成员的科学合作。技能 我将在指导阶段获得的奖项将使我唯一有资格回答重要的问题 有关宿主对病毒感染的反应的问题。 这项研究的科学目标是了解非造血细胞如何发挥抗病毒作用。 障碍物表面的免疫力。屏障表面是各种病毒的主要进入途径，而最初的 在这些部位引发的抗病毒反应可能对病毒在受感染宿主内的传播产生显著影响。 许多感染屏障表面的病毒最初在上皮细胞内复制。然而，抗病毒药物 这些细胞诱导的反应及其在防止病毒从感染的主要部位传播中的作用是 人们对此知之甚少。对上皮细胞抗病毒免疫的研究主要集中在其作用上。 干扰素(IFN)。然而，许多病毒编码的蛋白质可以阻止干扰素的表达。因此，我建议细胞 有其他机制来沟通感染情况，并在遇到病毒时限制病毒复制 阻断干扰素表达的病毒。这一建议是基于我的观察，抑制干扰素的病毒 IL-1的表达促进感染的上皮细胞释放IL-1细胞因子，IL-1 细胞因子可诱导人成纤维细胞处于抗病毒状态。我推测感染了干扰素的上皮细胞- 躲避病毒释放预先形成的IL-1细胞因子，在邻近的非 造血细胞。此外，我认为屏障组织中的局部IL-1R信号在 控制病毒从最初的感染地点传播。在这份提案中，我将探讨该模型的关键方面 抗病毒免疫力。！具体地说，我将确定IL-1机制的遗传和生化基础 从病毒感染的上皮细胞释放细胞因子(目标1)，决定了关键的 IL-1细胞因子诱导的抗病毒反应的调节因子转录因子IRF1被激活或抑制 目的2)，并明确非造血细胞IL-1受体(IL-1R)信号转导的抗病毒机制(S)。 人类皮肤(目标3)。这些研究的结果将为最早的相遇提供重要的洞察 在主机和病毒之间，并最终将为我作为一个独立的 调查员。