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Human GBPs in cell-autonomous immunity to intracellular bacterial pathogens

人类 GBP 对细胞内细菌病原体的细胞自主免疫

基本信息

批准号：
10468317
负责人：
Joern Coers
金额：
$ 45.89万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-01-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468317
关键词：
Actins Amino Acid Motifs Bacteria Binding Binding Proteins Biochemical Biochemical Genetics Biological Biological Assay Biological Response Modifiers Burkholderia C-terminal Cell Culture Techniques Cell Line Cells Chemicals Chimeric Proteins Cytosol Data Dynamin Epithelial Cells GBP1 gene Genetic Gram-Negative Bacteria Host Defense Host Defense Mechanism Human Immune Immune response Immune signaling Immunity In Vitro Infection Infection Control Inflammasome Interferons Intervention Lead Link Lipopolysaccharides Maps Mediating Modeling Modification Molecular Monitor Mus Nature Nucleic Acids O Antigens Pathway Analysis Pathway interactions Pattern Play Primates Process Production Proteins Publishing Reporting Research Role Shigella Shigella flexneri Signal Transduction Site Surface Tail Testing Time Work antagonist antimicrobial arms race bacterial genetics bactericide base cell motility chemokine genetic approach guanylate human disease immune function in vivo mouse model mutant novel novel strategies paracrine paralogous gene pathogen pathogenic bacteria polymerization prevent programs recruit resistance mechanism response tissue culture transcriptome sequencing

项目摘要

SUMMARY - Human GBPs as regulators of immunity to intracellular bacterial pathogens Guanylate binding proteins (GBPs) are host defense proteins that play diverse and critical roles in cell-autonomous immunity to intracellular bacterial pathogens. These proteins are major regulators of fundamental host defense modules and involved in processes such as inflammasome activation and the execution of direct bactericidal activities. However, almost all of this work has been performed in mouse models and antimicrobial functions of human GBPs (hGBPs) are still poorly characterized. In our recent studies we identified divergent host defense functions of the human GBPs and linked specific human GBPs to novel resistance mechanisms that protect against an important class of bacterial pathogens. Specifically, we found that human GBP1 (hGBP1) underpins two novel host defense mechanisms against cytosolic Gram-negative bacterial pathogens: 1) hGBP1 protein associates with cytosolic Gram- negative bacteria such as Shigella flexneri or Burkholderia thailandensis in the host cell cytosol. Once bound to bacteria, hGBP1 directly interferes with the actin-based intracellular motility of bacteria and thereby blocks bacterial dissemination; and 2) hGBP1 mediates activation of chemokine production by infected epithelial cells. Thus, hGBP1 activation appears to serve as a central node for two distinct but synergistic immune functions: a cell-intrinsic defense program prevents cell-to-cell spread of the pathogen while the production of paracrine immune signals promotes the activation and recruitment of immune cells to the site of infection. In this work, we will define the molecular mechanisms underlying these two important roles for hGBP1 that we have uncovered. In Aim1 we will combine cell culture and biochemical approaches to define the mechanism by which hGBP1 specifically detects Gram-negative bacteria in the host cell cytosol, a process critical for the inhibition of actin-based motility. In Aim2 we will characterize the mechanism by which hGBP1 bound to bacteria blocks actin-based motility. In Aim3 we will explore a second, independent function of hGBP1 as a novel regulator of an immune sensing pathway leading to the production of immune-modulatory chemokines using bacterial genetics, host genetics and cell biological approaches. In all of these studies we will take advantage of our recent discovery that the S. flexneri effector protein IpaH9.8 antagonizes hGBP1 function. Therefore, the use of IpaH9.8- deficient S. flexneri strains will enable us to monitor and functionally dissect an operational hGBP1-driven host response. Overall, the work proposed here will provide a fundamental understanding of the role of hGBP1 and other human GBPs in cell-autonomous immunity to intracellular bacterial pathogens. !

摘要：人GBPs作为对细胞内细菌病原体免疫的调节因子