Pathogen-induced immune and stress responses mediated by bZIP transcription factors

bZIP 转录因子介导的病原体诱导的免疫和应激反应

• 批准号: 10676256
• 负责人: Ransome van der Hoeven
• 金额: $ 39万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676256
• 关键词: ATF2 gene; Acute suppurative arthritis due to bacteria; Address; Alveolar; Antibiotics; Bacteremia; Bacteria; Biochemical; Biological Models; Blood; Caenorhabditis elegans; Cancer Patient; Cardiac Myocytes; Cell Death; Cell Line; Cell physiology; Cells; Cellular Stress; Cellulitis; Cessation of life; Clinical; Dedications; Development; Disease; Endocarditis; Epithelial Cells; Fibroblasts; Functional disorder; Genetic; Gingiva; Homeostasis; Human; Hydrogen Peroxide; Immune; Immune response; Immunocompromised Host; Infection; Infective endocarditis; Ingestion; Innate Immune Response; Intestines; Invaded; Laboratories; Link; Lung; Macrophage; Mammals; Mediating; Metabolic; Metabolism; Mus; Nematoda; Oral cavity; Organism; Oropharyngeal; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Post-Transcriptional Regulation; Predisposition; Production; Proteins; Regulation; Research Personnel; Resistance; Role; Sepsis; Signal Pathway; Stream; Streptococcus; Streptococcus mitis; Streptococcus oralis; Streptococcus pneumoniae; Stress Response Signaling; Testing; Therapeutic; Time; Tissues; Virulence Factors; Whole Organism; Work; biological adaptation to stress; chemotherapy; clinically significant; combat; community acquired pneumonia; cytotoxicity; human disease; immune activation; member; microorganism; model organism; novel; novel therapeutic intervention; opportunistic pathogen; oral bacteria; pathogen; response; transcription factor

Project Description The mitis group streptococci are ubiquitous microorganisms that colonize the human oropharynx. In susceptible hosts, these organisms are important opportunistic pathogens and they have shown to cause a wide range of infectious complications in humans, which includes bacteremia, orbital cellulitis, septic arthritis, and infective endocarditis. However, despite the clinical significances of these infections, the mechanisms of pathogenesis and the pathophysiology are poorly understood. Hydrogen peroxide (H2O2) produced by these microorganisms has been identified as an important virulence factor. Furthermore, H2O2 produced by members of this group such as Streptococcus oralis and Streptococcus mitis induced epithelial cell and macrophage death, while H2O2 produced by Streptococcus pneumoniae had a profound effect on the activation of cellular stress pathways in lung epithelial cells. The genetically tractable model organism Caenorhabditis elegans provides an opportunity to characterize the pathophysiology in context of the whole organism and to elucidate how non-immune cells facilitate innate immune and stress responses. In this study, we propose to elucidate mechanisms of activation of pathogen-induced immune and stress responses by the mitis group streptococci. Our central hypothesis is that immune and oxidative stress responses are mediated by the bZIP transcription factors ZIP-2 and ZIP-10 via pathogen-derived H2O2. To address our hypothesis the following aims will be tested; Specific Aim #1. To elucidate the mechanism how the bZIP transcription factor, ZIP-2 mediates the effector-triggered immune response in C. elegans against streptococcal-derived H2O2. Specific Aim #2. We will determine the mechanisms of activation of an immune and oxidative stress response via the bZIP transcription factor ZIP-10 in response to the pathogen-derived H2O2 in the worm. Specific Aim #3. To demonstrate the conservation of these mechanisms identified in aims 1 and 2 in human gingival fibroblasts. The proposed study is significant because we will identify how H2O2 produced by the mitis group streptococci causes pathogen-associated disruption of cellular processes and in turn the activation of protective mechanisms. Elucidating the protective mechanisms will help identify novel therapeutic strategies to combat these pathogens.

项目描述 轻链球菌是人类口咽部普遍存在的微生物。处于易感状态 宿主，这些生物体是重要的机会病原体，它们已被证明可引起广泛的 人类感染性并发症，包括菌血症、眼眶蜂窝织炎、化脓性关节炎和感染性关节炎 心内膜炎。然而，尽管这些感染具有临床意义，但其发病机制 且对其病理生理学知之甚少。这些微生物产生的过氧化氢 (H2O2) 已被确定为重要的毒力因子。此外，该组成员产生的 H2O2 口腔链球菌和轻链球菌诱导上皮细胞和巨噬细胞死亡，而H2O2 肺炎链球菌产生的对细胞应激途径的激活具有深远的影响 肺上皮细胞。遗传上易于处理的模式生物秀丽隐杆线虫提供了一个机会 描述整个生物体的病理生理学特征，并阐明非免疫细胞如何 促进先天免疫和应激反应。在这项研究中，我们建议阐明激活机制 轻症链球菌病原体诱导的免疫和应激反应。我们的中心假设是 免疫和氧化应激反应是由 bZIP 转录因子 ZIP-2 和 ZIP-10 介导的 病原体衍生的 H2O2。为了解决我们的假设，将测试以下目标：具体目标#1。到 阐明bZIP转录因子ZIP-2介导效应子触发免疫的机制 线虫对链球菌衍生的 H2O2 的反应。具体目标#2。我们将确定机制 通过 bZIP 转录因子 ZIP-10 激活免疫和氧化应激反应 蠕虫体内源自病原体的 H2O2。具体目标#3。为了证明这些资源的保护 目标 1 和 2 中在人类牙龈成纤维细胞中确定的机制。拟议的研究意义重大，因为 我们将确定 mitis 群链球菌产生的 H2O2 如何导致病原体相关的破坏 细胞过程，进而激活保护机制。阐明保护机制 将有助于确定对抗这些病原体的新治疗策略。