Sphingosine-1-phosphate signaling in pertussis pathogenesis and therapeutics

 描述（由申请人提供）：最近百日咳流行和幼儿死亡突出了这种疾病作为一个严重的重新出现的公共卫生问题。然而，对于百日咳的治疗不存在有效的疗法。由于抗生素治疗是无效的（症状持续很长时间后，细菌清除），宿主靶向治疗可能是必要的治疗百日咳疾病。这种疗法的潜在宿主靶点是鞘氨醇-1-磷酸（S1 P）受体信号传导。S1 P是一种鞘脂，通过G蛋白偶联受体（GPCR）结合并发出信号，这种信号可以减轻各种模型中的呼吸道炎症病理。例如，在脂多糖诱导的急性肺损伤和流感病毒感染的小鼠模型中，使用S1 P受体激动剂治疗可以增加肺血管屏障的完整性并减少肺部炎症病理。一种S1 P相关激动剂FTY 720在人类中用作多发性硬化症的治疗，其他相关激动剂正在进行各种炎症性疾病的高级临床试验，证明了这种方法的转化潜力。在初步研究中，我们发现，在细菌接种后不久用S1 P受体激动剂治疗百日咳杆菌感染的小鼠，显著降低了感染高峰时的炎症基因表达和肺部病理学。因此，我们假设用S1 P受体激动剂治疗百日咳感染的小鼠将减少肺部炎症病理，这可能代表了一种新的宿主导向的治疗百日咳的治疗靶点。 S1 P通过5个GPCR信号传导，这些GPCR与Gi亚类的异源三聚体G蛋白偶联。Gi蛋白是百日咳毒素修饰的特异性靶蛋白 (PT)是B的主要毒力因子。百日咳。在没有感染的情况下，PT给药不会引起呼吸道病理学，但在感染期间，它会抑制G蛋白信号传导，并引起百日咳疾病的各种局部和全身表现。我们已经证明PT在B中起主要作用。百日咳感染和呼吸道发病机制通过多重抑制作用对宿主的感染反应。使用成年小鼠模型比较野生型和PT缺陷型B的呼吸道感染。在百日咳菌株中，我们发现PT的产生与B峰处的炎症反应加剧有关。百日咳感染，且PT延长了炎性气道病理持续时间。这些数据表明，PT可以抑制减轻呼吸道炎症的宿主机制。基于S1 P受体信号传导在减弱上述炎症病理学中的已知特性，我们假设S1 P可能在限制B期间的炎症中发挥作用。百日咳感染，但PT抑制肺中S1 P受体信号传导阻止了这种减弱并加重了百日咳炎性病理。在这项探索性/开发性R21提案中，我们将开始研究这些假设，长期目标是开发急需的新型百日咳宿主靶向治疗药物。

 DESCRIPTION (provided by applicant): Recent pertussis epidemics and fatalities in young infants highlight this disease as a serious re-emerging public health issue. However, no effective therapies exist for treatment of pertussis. Since antibiotic therapy is ineffective (symptoms persist long after bacterial clearance), host-targeted therapeutics may be necessary to treat pertussis disease. A potential host target for this therapy is sphingosine-1- phosphate (S1P) receptor signaling. S1P is a sphingolipid that binds and signals through G protein-coupled receptors (GPCR), and this signaling can attenuate respiratory inflammatory pathology in various models. For instance, treatment with S1P receptor agonists increases pulmonary vascular barrier integrity and reduces lung inflammatory pathology in mouse models of LPS-induced acute lung injury and influenza virus infection. An S1P-related agonist, FTY720, is in use in humans as a therapy for multiple sclerosis, and other related agonists are in advanced clinical trials for a variety of inflammatory diseases, demonstrating the translational potential o this approach. In preliminary studies, we have found that treatment of Bordetella pertussis-infected mice with an S1P receptor agonist soon after bacterial inoculation significantly reduced inflammatory gene expression and lung pathology at the peak of infection. Therefore, we hypothesize that treatment of pertussis-infected mice with S1P receptor agonists will reduce lung inflammatory pathology and that this may represent a novel host-directed therapeutic target for treatment of pertussis. S1P signals through 5 GPCRs that couple to heterotrimeric G proteins of the Gi subclass. Gi proteins are the specific target of modification by pertussis toxin (PT), a major virulence factor of B. pertussis. PT administration in the absence of infection does not cause respiratory pathology, but during infection it inhibits G protein signaling and causes various local and systemic manifestations of pertussis disease. We have shown that PT plays a major role in B. pertussis infection and respiratory pathogenesis through multiple inhibitory effects on host responses to infection. Using adult mouse models to compare respiratory infection by wild type and PT-deficient B. pertussis strains, we found that PT production is associated with exacerbated inflammatory responses at the peak of B. pertussis infection, and that PT prolongs the duration of inflammatory airway pathology. These data indicate that PT may inhibit host mechanisms of attenuating inflammation in the respiratory tract. Based on the known properties of S1P receptor signaling in attenuating inflammatory pathology described above, we hypothesize that S1P can potentially play a role in limiting inflammation during B. pertussis infection, but that PT inhibition of S1P receptor signaling in the lungs prevents this attenuation and exacerbates pertussis inflammatory pathology. In this exploratory/developmental R21 proposal, we will begin to investigate these hypotheses with a long- term goal of developing much needed novel host-targeted therapeutics for pertussis.