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: 10366502
• 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/10366502
• 关键词: ATF2 gene; Acute suppurative arthritis due to bacteria; Address; Alveolar; Animal Model; Antibiotics; Bacteremia; Bacteria; Biochemical; Biological Models; Blood; Caenorhabditis elegans; Cancer Patient; Cardiac Myocytes; Cell Death; Cell physiology; Cells; Cellular Stress; Cellular Stress Response; Cellulitis; Cessation of life; Clinical; 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; Mammals; Mediating; Metabolic; Metabolism; Mouse Cell Line; Nematoda; Oral cavity; Organism; Oropharyngeal; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Post-Transcriptional Regulation; Post-Translational Regulation; 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; macrophage; member; microorganism; 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 缓症组链球菌是普遍存在于人类口咽部的微生物。易感 宿主，这些生物体是重要的机会致病菌，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、脓毒性关节炎和感染性 心内膜炎然而，尽管这些感染的临床意义，发病机制， 和病理生理学都知之甚少。这些微生物产生的过氧化氢（H2 O2） 已被确定为一个重要的毒力因子。此外，由该组成员产生的H2 O2， 口腔链球菌和缓症链球菌引起上皮细胞和巨噬细胞死亡，而H2 O2 肺炎链球菌产生的一种对细胞应激途径的激活有深远的影响， 肺上皮细胞遗传上易处理的模式生物秀丽隐杆线虫提供了一个机会， 在整个生物体的背景下表征病理生理学，并阐明非免疫细胞 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， 病原体诱导的免疫和应激反应的缓和组链球菌。我们的核心假设是 免疫和氧化应激反应由bZIP转录因子ZIP-2和ZIP-10介导， 病原体来源的H2 O2。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如何介导效应子触发的免疫应答的机制。 响应C。elegans对抗链球菌衍生的H2 O2。具体目标#2我们将确定 通过bZIP转录因子ZIP-10激活免疫和氧化应激反应， 病原体产生的H2 O2具体目标#3为了证明这些 目标1和2中确定的人牙龈成纤维细胞中的机制。这项研究意义重大，因为 我们将确定由缓症链球菌产生的H2 O2如何引起病原体相关的破坏， 细胞过程，进而激活保护机制。阐明保护机制 将有助于确定新的治疗策略来对抗这些病原体。