Host-targeted therapeutics for pertussis in infants

婴儿百日咳的宿主靶向治疗

• 批准号: 9035033
• 负责人: NICHOLAS H CARBONETTI
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035033
• 关键词: Acute Lung Injury; Admission activity; Adult; Agonist; Blood Vessels; Bordetella pertussis; Case Study; Cell physiology; Cells; Cessation of life; Characteristics; Child; Complement Factor B; Data; Development; Disease; Disease Outcome; Employee Strikes; Epidemic; Focal Infection; G-Protein-Coupled Receptors; GTP-Binding Proteins; Heterotrimeric GTP-Binding Proteins; Hospitalization; Human; Immune; Immune response; Infant; Infection; Inflammatory; Leukocytosis; Lung; Lung Inflammation; Mediating; Modeling; Morbidity - disease rate; Mus; Organ; Outcome; Pathogenesis; Pathology; Pediatric Intensive Care Units; Pertussis; Pertussis Toxin; Play; Pulmonary Hypertension; Regulation; Research Proposals; Respiratory Signs and Symptoms; Respiratory System; Respiratory tract structure; Risk; Role; Signal Pathway; Signal Transduction; Sphingolipids; Sphingosine-1-Phosphate Receptor; Testing; Therapeutic; Vaccination; Virulence Factors; Virus Diseases; age group; effective therapy; influenzavirus; lung hypoxia; mouse model; novel therapeutic intervention; pathogen; public health relevance; sphingosine 1-phosphate; targeted treatment; therapeutic target; trafficking; treatment effect

 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.

 描述（由申请人提供）：小婴儿的百日咳可发展为复杂且严重的疾病（危重百日咳），通常需要住院治疗，并仍然造成惊人的死亡人数。最近的百日咳流行增加了小婴儿接触感染的可能性，这对于接种疫苗前的婴儿（<2 个月大）尤其危险。然而，尚无治疗危重百日咳的有效疗法。百日咳毒素 (PT) 是百日咳博德特氏菌的主要毒力因子，可抑制 G 蛋白信号并导致受感染婴儿白细胞显着增多，这种发病与不良预后相关。我们假设 PT 通过对感染和宿主反应的多重影响，在危重百日咳疾病的发病机制中发挥重要作用。我们的初步数据表明，PT促进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征。这反映了人类的百日咳疾病，婴儿容易患上严重疾病并死亡，但年龄较大的儿童和成人患上的疾病较轻，并且没有死亡。我们打算研究 PT 在幼年小鼠百日咳感染和疾病恶化中的作用。 PT 的宿主靶标是 1-磷酸鞘氨醇 (S1P) 信号传导，可能为百日咳提供治疗潜力，该信号传导由 G 蛋白偶联受体 (GPCR) 介导，而 GPCR 的信号传导被 ​​PT 抑制。 S1P 是一种鞘脂，参与调节血管屏障完整性、免疫细胞运输和其他一些细胞过程。在 LPS 诱导的急性肺损伤和流感病毒感染的小鼠模型中，使用 S1P 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。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年小鼠，可显着降低这种感染的致死率。因此，我们将研究 S1P 受体激动剂治疗对幼年小鼠百日咳疾病的潜在有益作用，并确定 S1P 信号传导的 PT 抑制是否会抑制这种有益作用。这项研究可能会确定治疗婴儿危重百日咳的新治疗方法。