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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：
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
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/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

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.

摘要