Host-targeted therapeutics for pertussis in infants

 描述(由申请人提供)：婴幼儿百日咳可发展为复杂和严重的疾病(危重百日咳)，通常需要住院治疗，但仍导致惊人的死亡人数。最近的百日咳流行增加了幼儿接触这种感染的可能性，这对接种前(两个月大)的婴儿尤其危险。然而，目前还没有治疗危重百日咳的有效方法。百日咳毒素(PT)是百日咳杆菌的主要毒力因子，它能抑制G蛋白信号转导系统，使感染婴儿出现严重的白细胞增多症，这一发病率与不良预后密切相关。我们推测PT通过对感染和宿主反应的多方面影响，在危重百日咳的发病机制中发挥重要作用。我们的初步数据表明，PT提高了幼年小鼠百日咳感染的致死率，但也揭示了幼年小鼠的百日咳感染和疾病具有与成年小鼠截然不同的特点。这反映了人类的百日咳疾病，婴儿容易患上严重的疾病和死亡，但年龄较大的儿童和成年人遭受的疾病不那么严重，没有死亡。我们建议研究PT在幼鼠百日咳感染和疾病加重中的作用。 PT的一个宿主靶点是鞘氨醇-1-磷酸(S1P)信号，它由G蛋白偶联受体(GPCR)介导，而G蛋白偶联受体的信号转导被PT抑制。S1P是一种鞘磷脂，参与调节血管屏障完整性、免疫细胞运输和其他几个细胞过程。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，并减少了肺部炎症。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的幼鼠显著降低了这种感染的致死率。因此，我们将研究S1P受体激动剂治疗幼年小鼠百日咳疾病的潜在益处，并确定PT抑制S1P信号是否抑制这一有益效果。这项研究可能确定治疗婴儿危重百日咳的新方法。

 DESCRIPTION (provided by applicant): Pertussis in young infants can progress to complicated and severe disease (critical pertussis), often requiring hospitalization and still causing an alarming number of deaths. Recent pertussis epidemics increase the likelihood of exposure of young infants to the infection, which is especially dangerous to pre-vaccination infants (<2 mo old). However, no effective therapies exist for treatment of critical pertussis. Pertussis toxin (PT), a major virulence factor of Bordetella pertussis, inhibits G protein signalin and causes dramatic leukocytosis in infected infants, a morbidity that correlates with poor outcome. We hypothesize that PT plays a major role in the pathogenesis of critical pertussis disease through multiple effects on infection and host responses. Our preliminary data demonstrate that PT promotes lethality of pertussis infection in infant mice, but also reveal that pertussis infection and disease in infant mice have characteristics quite different from those in adult mice. This reflects pertussis disease in humans, where infants are susceptible to severe disease and death, but older children and adults suffer less severe disease and no deaths. We propose to study the role of PT in exacerbation of pertussis infection and disease in infant mice. A host target of PT that may provide therapeutic potential for treatment of pertussis is sphingosine-1-phosphate (S1P) signaling, which is mediated by G protein-coupled receptors (GPCR) whose signaling is inhibited by PT. S1P is a sphingolipid involved in regulation of vascular barrier integrity, immune cell trafficking, and several other cellular processes. Treatment with S1P receptor agonists increases pulmonary vascular barrier integrity and reduces lung inflammation in mouse models of LPS-induced acute lung injury and influenza virus infection. We have found that treatment of pertussis-infected infant mice with an S1P receptor agonist soon after bacterial inoculation significantly reduced lethality of this infection Therefore we will investigate the potentially beneficial effect of treatment with S1P receptor agonists on pertussis disease in infant mice, and determine whether PT inhibition of S1P signaling inhibits this beneficial effect. This study may identify novel therapeutic approaches to treatment of critical pertussis in infants.