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Novel roles for lipopolysaccharide modifications in immune evasion

脂多糖修饰在免疫逃避中的新作用

基本信息

批准号：
10592139
负责人：
Joern Coers
金额：
$ 20.66万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-17 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592139
关键词：
Acceleration Acylation Anti-Bacterial Agents Antibiotics Apolipoproteins Bacteria Bacterial Infections Bacterial Meningitis Binding Binding Proteins Biological Assay Biological Process Cell Death Cell Wall Cell secretion Cells Cellular Immunity Cerebrospinal Fluid Cytosol Data Detergents Disaccharides Drug Targeting Encapsulated Endothelial Cells Endotoxins Enzymes Epithelial Cells Extracellular Protein Fatty Acids Goals Gram-Negative Bacteria Host Defense Human Immune Immune Evasion Immune system Immunity In Vitro Infection Infection Control Inflammasome Innate Immune Response Interferons Kinetics Length Libraries Licensing Lipid A Lipids Lipopolysaccharides Macrophage Mass Spectrum Analysis Mediating Mediator Membrane Microcapsules drug delivery system Modification Molecular Target Multi-Drug Resistance Pathway interactions Patients Pattern recognition receptor Penetration Permeability Plasma Polymyxin B Protein Secretion Proteins Pseudomonas aeruginosa Pulmonary Cystic Fibrosis Resistance Role Route Salmonella typhimurium Shigella flexneri Side Structure Surface TLR4 gene Testing Therapeutic Virulence Factors Work antimicrobial antimicrobial peptide bacterial genetics candidate identification capsule cell type enteric pathogen extracellular genetic approach guanylate human pathogen inhibitor inorganic phosphate lipopolysaccharide-binding protein new therapeutic target novel novel strategies novel therapeutic intervention pathogen pathogenic bacteria polypeptide response screening surfactant synergism targeted treatment treatment strategy

项目摘要

The outer membrane of Gram-negative bacteria forms a permeability barrier blocking antimicrobials from efficiently reaching their molecular targets residing within the bacterial cell wall or inside the bacterial cytosol. This barrier function is dependent on one of the outer membrane’s central building blocks, lipopolysaccharide (LPS). The LPS molecule is anchored in the outer bacterial membrane by its lipid A moiety. Lipid A, an acylated disaccharide, is sensed by the pattern recognition receptor TLR4 of the human immune system. To avoid TLR4 sensing, bacteria evolved mechanisms to modify their lipid A structure, for example by changing the number or lengths of its fatty acid side chains, or adding or removing terminal phosphate moieties. However, not all LPS modifications are important for TLR4 avoidance and the biological function of many LPS modifications is only poorly characterized. This proposal will test the novel hypothesis that specific lipid A modifications enable bacteria to escape from host immunity exerted by human guanylate binding protein 1 (GBP1). We recently showed that GBP1 is an additional bona fide LPS-binding protein. Intracellular GBP1 executes at least two functions: i) it accelerates the kinetics of LPS-mediated inflammasome activation and ii) it binds directly to the surface of cytosolic Gram- negative bacteria, where it acts as a surfactant operating synergistically with antimicrobials that need to penetrate the bacterial outer membrane. In Aim1 we will identify specific lipid A modifications that block the binding of GBP1 to the surface of two important human pathogens: the intracellular enteric pathogen Salmonella enterica Typhimurium and the extracellular pathogen Pseudomonas aeruginosa. GBP1 resides in the host cell cytosol but GBP1 is also secreted into the extracellular milieu. Secreted GBP1 can be found at high concentrations in plasma and cerebrospinal fluids of bacterial meningitis patients. However, the biological function of secreted GBP1 is unknown. Because we found that GBP1 binds to the extracellular bacterial pathogen Pseudomonas aeruginosa, we will test whether and how secreted GBP1 can exert host defense to extracellular bacteria in Aim2. Specifically, we will test the hypothesis that secreted GBP1 works synergistically with extracellular antimicrobial peptides. Conceptually related, Aim2 will also identify extant antibiotics that operate synergistically with GBP1. Together, Aims 1 and 2 provide a roadmap towards novel strategies for the treatment of many Gram-negative infections: targeting LPS-modifying enzymes involved in GBP1 evasion combined with the use of antibiotics that operate synergistically with GBP1.

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