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

基本信息

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
项目类别：
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

项目摘要

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，尽管成功的大规模疫苗接种计划。关键的百日咳疾病每年导致超过150,000人死亡。只有在特征性咳嗽开始之前给予抗生素才能有效。由于这些原因，有一个迫切需要开发新疗法。我们小组的长期目标是开发抗素疗法。我们的中心假设是针对细菌毒力因子引起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（S1PR）减少小鼠和狒狒肺部炎症的激动剂。这项工作的目的是了解S1PR激动剂介导的反应的有益元素，以指导下一代抗微生物。我们确定了两个肽聚糖识别蛋白（PGLYRP），-1和-4一个抗菌蛋白，由S1PR激动剂的差异调节。 PGLYRP通过与肽聚糖（PGN）。 pgylrp1而不是pglyrp4可以刺激PGN刺激炎症反应结合。我们假设PGLYRP4与PGLYRP1竞争以介导炎症反应。更远，我们建议这是通过抑制骨髓细胞1（TREM1）上宿主触发受体的抑制来介导的。 TREM-1是炎症反应的放大器。在模式识别受体之后，它被上调激活及其活性扩增炎症细胞因子的表达。 TREM-1配体包括PGLYRP1-PGN 复合物。 S1PR激动剂和抑制剂处理的小鼠降低了TREM-1的表达降低百日咳芽孢杆菌感染后的炎症病理学。我们假设TREM-1充当检查站在有益细菌控制和有害炎症病理学之间。