Regulation of Pulmonary Host Defenses by the Endoplasmic Reticulum Stress Sensor IRE1α

内质网应激传感器 IRE1α 对肺宿主防御的调节

• 批准号: 10653451
• 负责人: Basel Hanna Abuaita
• 金额: $ 30.93万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-24 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10653451
• 关键词: Abscess; Air Pollutants; Antibiotic Resistance; Asthma; Biology; Cellular Stress; Cellular Stress Response; Development; Disease; Ensure; Exposure to; Gases; Generations; Goals; Host Defense; Immune; Infection; Inflammation Mediators; Inflammatory; Inflammatory Response; Inhalation; Interleukin-1 beta; Investigation; Lung; Lung diseases; Lung infections; Mediating; Mitochondria; Modeling; Mus; Nosocomial Infections; Organ; Production; Reactive Oxygen Species; Regulation; Resolution; Role; Signal Transduction; Staphylococcus aureus infection; Testing; Tissues; United States; antimicrobial; bactericide; biological adaptation to stress; endoplasmic reticulum stress; extracellular; idiopathic pulmonary fibrosis; in vivo; insight; macrophage; methicillin resistant Staphylococcus aureus; neutrophil; new therapeutic target; novel therapeutic intervention; pathogen; response; sensor

Methicillin-resistant Staphylococcus aureus (MRSA) infection is the leading cause of hospital-acquired infection worldwide. It causes approximately 14 million infections annually in the United States alone. Increasing antibiotic resistance in this pathogen highlights a compelling need to identify new therapeutic targets to treat MRSA infections. We recently showed that the endoplasmic reticulum (ER) stress sensor, IRE1α, is a key component in innate immune defense against MRSA in macrophages, neutrophils, and in a murine abscess model of infection. We found that IRE1α controls macrophage and neutrophil antimicrobial functions by enhancing production of inflammatory molecules including mitochondrial reactive oxygen species (MitoROS), neutrophil extracellular traps (NETs), and IL-1β, which are essential for resolving MRSA infection in vivo. In the lung, ER stress occurs during infection, air pollutant inhalation and during the development of many pulmonary diseases like Idiopathic Pulmonary Fibrosis and Asthma. However, how IRE1α is involved in progression and resolution of lung diseases is not well understood. Because the lung is a vital organ, macrophages and neutrophils must adequately tune their responses to ensure effective antimicrobial function without excessive tissue damage that could inhibit gas exchange. Therefore, investigation of IRE1α-mediated stress responses during lung infection will lend valuable mechanistic insight into the regulation of pulmonary host defenses. The overarching goal of this proposal is to elucidate the role of IRE1α in pulmonary host defenses during MRSA infection. Our central hypothesis is that infection triggers IRE1α signaling, which enhances lung innate immune effector functions includes bactericidal activity and production of inflammatory mediators. We will accomplish the following Aims to test our hypothesis: (1) Characterize the requirement of IRE1α activation and MitoROS generation to lung macrophage inflammatory responses, and (2) Elucidate whether the IRE1α circuit aids or impedes innate immune defense against pulmonary MRSA infection. Completing this study will establish the ER stress response as an important regulatory network in lung host defense and will lay the groundwork for further studies in the intersection between cellular stress response and lung diseases.

耐甲氧西林金黄色葡萄球菌（MRSA）感染是全球医院获得性感染的主要原因。仅在美国，每年就有大约1400万例感染。这种病原体不断增加的抗生素耐药性凸显了迫切需要确定新的治疗靶点来治疗MRSA感染。我们最近发现，内质网（ER）应激传感器IRE1α是巨噬细胞、中性粒细胞和小鼠脓肿感染模型中抵抗MRSA的先天免疫防御的关键成分。我们发现IRE1α通过增强炎症分子的产生来控制巨噬细胞和中性粒细胞的抗菌功能，这些炎症分子包括线粒体活性氧（MitoROS）、中性粒细胞胞外陷阱（NETs）和IL-1β，这些炎症分子对体内解决MRSA感染至关重要。在肺部，内质网应激发生在感染、空气污染物吸入以及许多肺部疾病如特发性肺纤维化和哮喘的发展过程中。然而，IRE1α如何参与肺部疾病的进展和解决尚不清楚。由于肺是一个重要器官，巨噬细胞和中性粒细胞必须充分调整它们的反应，以确保有效的抗菌功能，而不会过度损伤可能抑制气体交换的组织。因此，研究ire1 α-介导的肺部感染应激反应将为了解肺宿主防御的调控机制提供有价值的见解。本提案的总体目标是阐明IRE1α在MRSA感染期间肺宿主防御中的作用。我们的中心假设是感染触发IRE1α信号，从而增强肺固有免疫效应功能，包括杀菌活性和炎症介质的产生。我们将完成以下目标来验证我们的假设：(1)表征IRE1α激活和MitoROS生成对肺巨噬细胞炎症反应的要求；(2)阐明IRE1α回路是否有助于或阻碍对肺部MRSA感染的先天免疫防御。本研究的完成将确立内质网应激反应作为肺宿主防御的重要调控网络，为进一步研究细胞应激反应与肺部疾病的交叉关系奠定基础。