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: 10556372
• 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/10556372
• 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; Licensing; 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; Trachea; Virulence Factors; Work; airway epithelium; antimicrobial; antimicrobial peptide; associated symptom; bactericide; 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.

项目摘要 近年来，百日咳作为一个主要的公共卫生问题重新出现，尽管 成功的大规模疫苗接种计划。严重的百日咳每年造成15万多人死亡。 抗生素只有在特征性咳嗽发作前使用才有效。由于这些原因， 迫切需要开发新的治疗方法。 我们小组的长期目标是开发抗百日咳疗法。我们的核心假设是， 靶向由细菌毒力因子诱导的组织损伤和炎症将具有比 传统的杀菌疗法。我们已经证明了鞘氨醇-1-磷酸受体的潜力 （S1 PR）激动剂在减少小鼠和狒狒的肺部炎症中的作用。这项工作的目标是 了解S1 PR激动剂介导的反应的有益因素，以指导下一代抗- 微生物我们鉴定了两种肽聚糖识别蛋白（PGLYRP），-1和-4，一种抗菌蛋白， 受S1 PR激动作用的差异调节。PGLYRPs通过与以下物质的相互作用引发杀菌活性： 肽聚糖（PGN）。PGYLRP 1而不是PGLYRP 4可以刺激PGN后的炎症反应 约束力我们假设PGLYRP 4与PGLYRP 1竞争介导炎症反应。此外，本发明还 我们提出这是通过抑制髓样细胞上的宿主触发受体1（TREM 1）介导的。 TREM-1是炎症反应的放大器。它在模式识别受体 其活化和活性放大炎性细胞因子表达。TREM-1配体包括PGLYRP 1-PGN 配合物TREM-1表达通过S1 PR激动而降低，并且抑制剂处理的小鼠显示降低的TREM-1表达。 B.百日咳感染我们假设TREM-1作为检查点 有益的细菌控制和有害的炎症病理之间的关系。