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