Role of epithelial cell intracellular trafficking in the innate immune response to adenovirus infection

上皮细胞胞内运输在腺病毒感染先天免疫反应中的作用

• 批准号: 10549310
• 负责人: CATHLEEN R CARLIN
• 金额: $ 36.83万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549310
• 关键词: Accounting; Address; Adenovirus Infections; Adenovirus Vector; Adenoviruses; Adult; Antiviral Therapy; Apical; Attenuated; Autophagocytosis; Back; Biological; Biological Process; Calmodulin; Cell Adhesion; Cell Polarity; Cell membrane; Cell model; Cells; Cellular Stress; Chronic lung disease; Clathrin Adaptors; Clinical; Cyclic AMP-Dependent Protein Kinases; Cytoskeleton; Data; Development; Disease; Docking; Endoplasmic Reticulum; Endosomes; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Exhibits; Exposure to; Failure; Future; GAB1 gene; Genes; Genetic Transcription; Goals; Human; Immune; Immune response; Immune signaling; Individual; Infectious Agent; Inflammatory; Innate Immune Response; Innate Immune System; Invaded; Knowledge; Lead; Ligands; Link; Lung infections; Malignant Neoplasms; Mammalian Cell; Medical; Membrane; Membrane Proteins; Modeling; Molecular; Molecular Conformation; Multivesicular Body; Natural Immunity; Oncolytic; Pathogenesis; Pathologic; Pathway interactions; Physiological; Play; Process; Protein Sortings; Proteins; Receptor Signaling; Recombinants; Recycling; Research; Respiratory Disease; Respiratory System; Respiratory Tract Infections; Role; Serotyping; Signal Pathway; Signal Transduction; Sorting; Stimulus; Stress; Surface; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transplant Recipients; Virus; airway epithelium; airway immune response; apical membrane; basolateral membrane; beta catenin; biological adaptation to stress; cytokine; design; endosome membrane; ezrin; gene product; gene therapy clinical trial; human disease; innate immune function; insight; new therapeutic target; novel; novel therapeutics; pathogen; protein activation; public health relevance; receptor; receptor expression; receptor function; release of sequestered calcium ion into cytoplasm; respiratory; response; src-Family Kinases; trafficking; transcytosis

ABSTRACT The apical surface of polarized epithelium constitutes one of the first points of contact between the host and pathogens such as human adenoviruses (HAdVs) that invade the lumen of the respiratory tract. In recent years, it has become clear that respiratory epithelial cells not only serve as functional and physical barriers, but actively contribute to the innate immune system providing initial protection against external pathogens. The EGF receptor (EGFR), which typically exhibits basolateral polarity, has emerged as a key player in the innate immunity of respiratory epithelium to a variety of infectious and noninfectious noxious stimuli. In contrast to the canonical ligand-stimulated EGFR pathway, a number of cellular stresses including HAdV infection (our studies) trigger an alternative mode of EGFR trafficking associated with sustained EGFR activity in non- degradative endosomes. However, molecular mechanisms regulating this pathway remain poorly understood. In addition, despite significant progress in understanding the pathological and therapeutic stresses that activate it, relatively little is known about EGFR function in the context of cellular stress. We have recently found that stress-induced EGFR signaling is involved in innate immune responses triggered by HAdV cell entry, as well as following exposure to the pro-inflammatory cytokine TNF-α, in respiratory epithelial cells. Moreover, HAdV encodes an early gene product that suppresses this pathway by promoting EGFR degradation, and which could provide new insights to potential targets for future anti-viral therapies. Interestingly, our preliminary studies have revealed that EGFR stress responses were tightly regulated by epithelial cell polarity, with robust stress-induced EGFR responses only observed when receptors were mistargeted to apical membranes. In addition, HAdV co-opted cellular pathways contributing to innate immune signaling by enabling dynamic EGFR membrane remodeling associated with enhanced stress-induced EGFR signaling from apical membranes. The newly described EGFR innate immune system is likely to have a central role in protecting the lung from infection with HAdVs and perhaps other pathogens. Conversely, failure to curb this signaling network may lead to tissue damage, respiratory compromise, and potentially systemic HAdV infections. Our research plan will identify novel mechanisms regulating dynamic EGFR membrane remodeling in polarized epithelial cells (Aim 1), and stress-induced EGFR innate immune signaling from endosomes (Aim 2); and analyze EGFR innate immune signaling pathways that are activated as a consequence of HAdV infection in primary human respiratory epithelial cells and new physiological cells models with enhanced apical EGFR expression (Aim 3). Although our studies will be carried out in the context of HAdVs, successful completion of this project will have a broad impact on a variety of respiratory conditions in need of new therapies.

摘要 极化上皮的顶端表面构成宿主与宿主之间的第一个接触点之一 病原体，如侵入呼吸道内腔的人腺病毒（HAdV）。近几 多年来，已经清楚的是，呼吸道上皮细胞不仅作为功能和物理屏障， 积极促进先天免疫系统提供初步保护，抵御外部病原体。的 表皮生长因子受体（EGFR），通常表现出基底侧极性，已成为先天性的关键球员， 呼吸道上皮对各种感染性和非感染性有害刺激的免疫力。相对于 典型的配体刺激的EGFR途径，许多细胞应激，包括HAdV感染（我们的 研究）触发了EGFR的另一种运输模式，与非肿瘤组织中持续的EGFR活性相关。 降解内体。然而，调控这一途径的分子机制仍然知之甚少。 此外，尽管在理解激活神经元的病理和治疗压力方面取得了重大进展， 然而，关于EGFR在细胞应激背景下的功能知之甚少。我们最近发现， 应激诱导的EGFR信号传导也参与HAdV细胞进入引发的先天性免疫应答 在呼吸道上皮细胞中，与暴露于促炎细胞因子TNF-α后一样。此外，HAdV 编码通过促进EGFR降解抑制该途径的早期基因产物， 可以为未来抗病毒治疗的潜在靶点提供新的见解。有趣的是，我们的初步 研究表明，EGFR应激反应受到上皮细胞极性的严格调控， 应激诱导的EGFR反应仅在受体错误定位于顶膜时观察到。在 此外，HAdV通过激活动态EGFR， 膜重塑与来自顶膜的增强的应激诱导的EGFR信号传导相关。 新描述的EGFR先天免疫系统可能在保护肺免受 HAdV和其他病原体的感染。相反，如果不能控制这个信号网络， 组织损伤、呼吸系统损害和潜在的全身HAdV感染。我们的研究计划将 鉴定调节极化上皮细胞中动态EGFR膜重塑的新机制（Aim 1）和来自内体的应激诱导的EGFR先天免疫信号传导（Aim 2）;并分析EGFR先天免疫信号传导（Aim 1）。 HAdV感染后激活的免疫信号通路 呼吸道上皮细胞和具有增强的顶端EGFR表达的新生理细胞模型（Aim 3）。 虽然我们的研究将在HAdV的背景下进行，但成功完成该项目将 对需要新疗法的各种呼吸系统疾病产生广泛影响。