Identification of novel type III IFN regulatory pathways

摘要 干扰素（IFN）跨越维持细胞完整性的保护性反应和细胞内的细胞毒性之间的平衡。 诱导有害的炎症反应，导致不可逆的组织损伤。病毒检测 感染或细胞应激的积累触发I型（IFN γ/IFN γ）和III型IFN的合成 (IFNλ），其激活重叠的JAK/STAT途径以诱导称为 干扰素刺激基因（ISG）。虽然几乎所有的有核细胞都能对IFN γ/IFN γ刺激产生反应，但IFN γ/IFN γ刺激的细胞因子水平并不高。 IFN γ受体（IFNLR 1）的表达局限于少数细胞类型，主要是上皮细胞。研究 重叠IFN功能的进化要求揭示了IFN的背景特异性功能：IFN γ/IFN β 驱动抗病毒和促炎反应，在不减弱时可促进组织损伤， 赋予抗病毒保护作用，炎症诱导最小，并增强屏障的完整性。我 以前的工作已经确定了典型转录因子（TF）、干扰素调节因子（IFN）和转录因子（NF）的不同激活是如何发生的。 因子（IRF）和信号转导和转录激活因子（STAT），指定适应不良的IFN γ/IFN γ 功能协调发展的IFNλ反应也变得适应不良，阻碍屏障修复，但了解如何 平行的信号事件和细胞特性破坏了IFNλ病理生理功能的平衡， 缺乏我未来的工作将利用多学科的方法来填补这一知识空白。我们将决定 非典型信号整合，如NF-kB和MAPK，如何定义IFNλ依赖性屏障功能， 2)定义细胞特性如何控制细胞因子敏感性，以及3）利用遗传学来识别新的细胞类型 特异性的、非典型的TF和染色质修饰剂，其进入IFNλ反应。这些研究将 增强我们对IFN的共同和独特功能的基本理解，确定细胞的亲和性， 炎症损伤，并指导治疗干预措施的发展， 抑制炎症反应，同时保留IFN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.