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

项目摘要 近年来，百日咳再次成为一个主要的公共卫生问题，尽管 成功的大规模疫苗接种计划。危重百日咳每年造成超过15万人死亡。 抗生素只有在典型咳嗽开始之前服用才有效。出于这些原因，有一种 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。我们的中心假设是 以细菌毒力因子引起的组织损伤和炎症为靶点将比 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)激动剂，可减轻小鼠和狒狒的肺部炎症。这项工作的目标是 了解S1PR激动剂介导的反应的有益成分，以指导下一代抗- 微生物。我们鉴定了两个肽聚糖识别蛋白(PGLYRP)，-1和-4，一个抗菌蛋白， 受S1PR激动剂的差异调节。PGLYRPs通过与其相互作用诱导杀菌活性 肽聚糖(PGN)。PGYLRP1而不是PGLYRP4可刺激PGN后的炎症反应 有约束力的。我们假设PGLYRP4与PGLYRP1竞争介导炎症反应。此外， 我们认为这是通过抑制宿主触发的髓样细胞受体1(TREM1)来实现的。 TREM-1是炎症反应的放大因子。它随着模式识别受体的上调而上调 活化及其活性可增强炎性细胞因子的表达。TREM-1配体包括PGLYRP1-PGN 复合体。S1PR激动剂和抑制剂处理的小鼠TREM-1表达降低 百日咳杆菌感染后的炎性病理。我们假设TREM-1作为一个检查站 在有益的细菌控制和有害的炎症病理之间。

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.