Pertussis inflammation is mediated by a balance between peptidoglycan recognition proteins-1 and -4

百日咳炎症是由肽聚糖识别蛋白-1 和 -4 之间的平衡介导的

• 批准号: 10416387
• 负责人: Ciaran Skerry
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10416387
• 关键词: Agonist; Amplifiers; Antibiotic Therapy; Antibiotics; Attenuated; Binding; Biological Assay; Biosensor; Bordetella pertussis; Cause of Death; Cell Separation; Cells; Cessation of life; Characteristics; Communicable Diseases; Complex; Core Facility; Coughing; Cytotoxin; Data; Development; Disease; Elements; Equilibrium; Family; Flow Cytometry; Genes; Goals; Gram-Negative Bacteria; Immunization Programs; Infant; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Knockout Mice; Ligands; Lung; Mass Vaccinations; Measures; Mediating; Mus; Myeloid Cells; Papio; Pathogenesis; Pathology; Pattern recognition receptor; Peptidoglycan; Pertussis; Pharmaceutical Preparations; Proteins; Public Health; Pulmonary Inflammation; Pulmonary Pathology; Receptor Activation; Recombinants; Role; Sphingosine-1-Phosphate Receptor; Testing; Therapeutic; Tissues; Virulence Factors; Work; airway epithelium; antimicrobial; antimicrobial peptide; associated symptom; bactericide; base; cell type; cytokine; cytotoxic; differential expression; in vitro Assay; inhibitor; insight; next generation; novel therapeutics; peptidoglycan monomer; peptidoglycan recognition protein; prevent; receptor; response; single-cell RNA sequencing; transcriptomics

Project Summary Recent years have seen a re-emergence of pertussis as a major public health concern, despite successful mass vaccination programs. Critical pertussis disease causes over 150,000 deaths annually. Antibiotics are only effective if given before the onset of the characteristic cough. For these reasons, there is an urgent need for the development of new treatments. The long-term goal of our group is to develop anti-pertussis therapeutics. Our central hypothesis is that targeting tissue damage and inflammation induced by bacterial virulence factors will have a greater benefit than traditional bactericidal therapies. We have demonstrated the potential of sphingosine-1-phosphate receptor (S1PR) agonists in reducing pulmonary inflammation in mice and baboons. The objective of this work is to understand the beneficial elements of the S1PR agonist-mediated response to guide the next generation of anti- microbials. We identified two peptidoglycan recognition proteins (PGLYRP), -1, and -4 an antimicrobial protein, as differentially regulated by S1PR agonism. PGLYRPs elicit bactericidal activity through interactions with peptidoglycan (PGN). PGYLRP1 but not PGLYRP4 can stimulate inflammatory responses following PGN binding. We hypothesize that PGLYRP4 competes with PGLYRP1 to mediate inflammatory responses. Further, we propose that this is mediated by inhibition of host triggering receptor on myeloid cells 1 (TREM1). TREM-1 is an amplifier of inflammatory responses. It is upregulated following pattern recognition receptor activation and its activity amplifies inflammatory cytokine expression. TREM-1 ligands include PGLYRP1-PGN complexes. TREM-1 expression is reduced by S1PR agonism and inhibitor treated mice show reduced inflammatory pathology following B. pertussis infection. We hypothesize that TREM-1 acts as a checkpoint between beneficial bacterial control and detrimental inflammatory pathology.

项目总结