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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

基本信息

批准号：
10209611
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
项目类别：
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/10209611
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 Cellular Stress Response Chronic lung disease Clathrin Adaptors Clinical Cyclic AMP-Dependent Protein Kinases Cytoskeleton Data Development Disease Docking Endoplasmic Reticulum Endosomes Epidermal Growth Factor Receptor Epithelial Epithelial Cells 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 diseases Lung infections Malignant Neoplasms Mammalian Cell Masks 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 System Respiratory Tract Infections Role Serotyping Signal Pathway Signal Transduction Sorting - Cell Movement Stimulus Stress Structure of respiratory epithelium Surface TNF gene Testing Therapeutic Therapeutic Intervention Tissues Transplant Recipients Virus apical membrane base basolateral membrane beta catenin biological adaptation to stress cytokine design 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

项目摘要

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.

抽象的极化上皮的顶面构成宿主和宿主之间的第一个接触点之一。侵入呼吸道内腔的病原体，例如人类腺病毒 (HAdV)。近来多年来，人们已经清楚呼吸道上皮细胞不仅充当功能和物理屏障，而且积极促进先天免疫系统，提供针对外部病原体的初步保护。这 EGF 受体 (EGFR) 通常表现出基底外侧极性，已成为先天性免疫调节的关键参与者。呼吸道上皮对各种感染性和非感染性有害刺激的免疫力。相比之下经典配体刺激的 EGFR 通路、许多细胞应激，包括 HAdV 感染（我们的研究）触发了一种与非EGFR持续活性相关的EGFR运输的替代模式降解内体。然而，调节该途径的分子机制仍然知之甚少。此外，尽管在理解激活的病理和治疗应激方面取得了重大进展然而，对于细胞应激背景下 EGFR 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 细胞进入触发的先天免疫反应呼吸道上皮细胞暴露于促炎细胞因子 TNF-α 后。此外，HAdV 编码一种早期基因产物，通过促进 EGFR 降解来抑制该途径，并且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节，具有强大的仅当受体错误定位于顶膜时，才会观察到应激诱导的 EGFR 反应。在此外，HAdV 通过启用动态 EGFR 来选择细胞途径，从而促进先天免疫信号传导膜重塑与顶膜应激诱导的 EGFR 信号传导增强相关。新描述的 EGFR 先天免疫系统可能在保护肺部免受感染 HAdV 或其他病原体。相反，如果未能遏制该信号网络，可能会导致组织损伤、呼吸系统损害和潜在的全身性 HAdV 感染。我们的研究计划将确定调节极化上皮细胞动态 EGFR 膜重塑的新机制（目标 1) 以及应激诱导的内体 EGFR 先天免疫信号传导（目标 2）；并分析 EGFR 先天性原代人类感染 HAdV 后被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（目标 3）。虽然我们的研究将在 HAdV 的背景下进行，但该项目的成功完成将对需要新疗法的各种呼吸系统疾病产生广泛影响。