Identification of novel type III IFN regulatory pathways

摘要 干扰素(IFN)在维持细胞完整性的保护性反应和 诱导有害的炎症反应，造成不可逆的组织损伤。病毒的检测 感染或细胞应激积累触发I型(干扰素/)和III型IFN的合成 (干扰素λ)，激活重叠的JAK/STAT途径，诱导称为 干扰素刺激基因(ISGs)。虽然几乎所有有核细胞都能对干扰素/刺激产生反应，但 干扰素受体的表达仅限于少数细胞类型，主要是上皮细胞。研究：关于 干扰素功能重叠的进化要求，揭示了干扰素/的上下文特定功能 推动抗病毒和促炎反应，在不减弱的情况下可能会促进组织损伤，以及干扰素λ 提供最低限度的炎症诱导的抗病毒保护，并加强屏障的完整性。我的 以前的工作已经定义了规范转录因子(TF)的不同激活方式，干扰素的调节 因子(IRF)和信号转导及转录激活子(STAT)，指定适应不良的干扰素/ 功能。干扰素λ反应也变得不适应，阻碍屏障修复，但了解如何 并行的信号事件和细胞特性破坏了干扰素λ病理生理功能的平衡 缺乏。我未来的工作将利用多学科方法来填补这一知识空白。我们将1)确定 非正则信号整合，如核因子-kB和丝裂原活化蛋白激酶，如何定义干扰素λ依赖的屏障功能， 2)定义细胞特性如何控制细胞因子的敏感性；3)利用遗传学识别新的细胞类型 提供给干扰素λ反应的特定的、非规范的转铁蛋白和染色质修饰物。这些研究将 增强我们对干扰素的共同和独特功能的基本了解，确定细胞对 炎症性损害，并指导开发抑制过度的治疗干预措施 炎症反应，同时保留了干扰素的原始抗病毒功能。

ABSTRACT Interferons (IFN) straddle the balance between protective responses that maintain cellular integrity and the induction of deleterious inflammatory responses that cause irreversible tissue damage. The detection of viral infection or the accumulation of cellular stress triggers the synthesis of both type I (IFN/) and type III IFNs (IFNλ), which activate an overlapping JAK/STAT pathway to induce the expression of effector genes known as interferon stimulated genes (ISGs). While almost all nucleated cells can respond to IFN/ stimulation, the expression of the IFN receptor (IFNLR1) is restricted to a few cell types, primarily the epithelium. Studies on the evolutionary requirement for overlapping IFN functions, revealed context-specific functions for IFNs: IFN/ drive antiviral and proinflammatory responses that can promote tissue damage when unabated, and IFNλ confers antiviral protection with minimal inflammatory induction and reinforces the integrity of the barrier. My previous work has defined how divergent activation of canonical transcription factors (TF), interferon regulatory factors (IRF) and Signal transducer and activator of transcription (STAT), specifies maladaptive IFN/ functions. IFNλ responses also become maladaptive and hinder barrier repair, yet understanding of how parallel signaling events and cell identity disrupt the balance of the IFNλ pathophysiological functions is lacking. My future work will utilize a multidisciplinary approach to fill this knowledge gap. We will 1) determine how non-canonical signal integration, such as NF-kB and MAPK, defines the IFNλ-dependent barrier functions, 2) define how cell identity controls cytokine sensitivity, and 3) leverage genetics to identify novel cell-type specific, non-canonical TF and chromatin modifiers that feed into the IFNλ response. These studies will enhance our basic understanding of the shared and unique functions of IFN, identify cellular susceptibilities to inflammatory damage, and guide the development of therapeutic interventions that dampen excessive inflammatory responses while preserving the primordial antiviral functions of IFNs.