Sphingosine-1-phosphate signaling in pertussis pathogenesis and therapeutics

 描述(由申请人提供)：最近的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，目前还没有有效的治疗百日咳的方法。由于抗生素治疗无效(细菌清除后症状持续很长时间)，宿主靶向治疗百日咳可能是必要的。这种疗法的一个潜在宿主靶点是鞘氨醇-1-磷酸(S1P)受体信号。S1P是一种神经鞘磷脂，通过G蛋白偶联受体(GPCR)结合并传递信号，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，S1P受体激动剂的治疗增加了肺血管屏障的完整性，减少了肺部炎症病理。一种与S1P相关的激动剂FTY720正在人类用于多发性硬化症的治疗，其他相关激动剂正在对各种炎症性疾病进行高级临床试验，证明了这种方法的翻译潜力。在初步研究中，我们发现，在细菌接种后不久，用S1P受体激动剂治疗感染百日咳杆菌的小鼠，显著减少了感染高峰期的炎症基因表达和肺部病理。因此，我们推测，用S1P受体激动剂治疗百日咳感染的小鼠可以减轻肺部炎症病理，这可能是治疗百日咳的一个新的宿主导向的治疗靶点。S1P通过与Gi亚类的异源三聚体G蛋白偶联的5个GPCRs来传递信号。Gi蛋白是百日咳毒素修饰的特异性靶点 (PT)是百日咳杆菌的主要毒力因子。PT在无感染的情况下给药不会引起呼吸道病理，但在感染期间它会抑制G蛋白信号转导，并导致百日咳疾病的各种局部和全身表现。我们已经证明PT在百日咳杆菌感染和呼吸道致病中起主要作用，它是通过抑制宿主对感染的反应而起作用的。使用成年小鼠模型比较百日咳杆菌野生型和PT缺乏株的呼吸道感染，我们发现PT的产生与百日咳杆菌感染高峰期的炎症反应加剧有关，并且PT延长了炎症呼吸道病理的持续时间。这些数据表明PT可能抑制宿主减轻呼吸道炎症的机制。基于上述S1P受体信号在减轻炎症病理中的已知特性，我们假设S1P在百日咳杆菌感染过程中可能发挥限制炎症的作用，但PT抑制肺内S1P受体信号可阻止这种减弱并加剧百日咳炎症病理。在这个探索性/发展性的R21方案中，我们将开始研究这些假说，长期目标是开发急需的新型宿主靶向疗法来治疗百日咳。

 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.