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）：幼儿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，并且仍然造成惊人的死亡人数。最近的百日咳流行增加了幼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，对于严重百日咳毒素（PT）（百日咳毒素的主要毒力因子）尚无有效的治疗方法。百日咳博德特氏菌抑制 G 蛋白信号并导致受感染婴儿的白细胞急剧增多，这种发病与不良结局相关。我们的初步数据表明，PT 通过对感染和宿主反应的多种影响，在危重百日咳疾病的发病机制中发挥着重要作用。证明PT促进幼年小鼠百日咳感染的致死率，同时也反映出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。在人类中，婴儿容易患严重疾病和死亡，但年龄较大的儿童和成人患的疾病较轻，并且不会死亡。我们建议研究 PT 在小鼠幼年百日咳感染和疾病恶化中的作用。 可能为百日咳治疗提供治疗潜力的 PT 宿主靶标是 1-磷酸鞘氨醇 (S1P) 信号传导，该信号传导由 G 蛋白偶联受体 (GPCR) 介导，而 S1P 是参与百日咳的鞘脂，其信号传导受到抑制。血管屏障完整性、免疫细胞运输和其他几种细胞过程的调节在小鼠模型中，使用 S1P 受体激动剂治疗可增加肺血管屏障的完整性并减少肺部炎症。 LPS 诱导的急性肺损伤和流感病毒感染。我们发现，在细菌接种后立即用 S1P 受体激动剂治疗感染百日咳的幼鼠可显着降低这种感染的致死率，因此我们将研究用 S1P 受体治疗的潜在有益效果。激动剂对婴儿小鼠百日咳疾病的影响，并确定 PT 抑制 S1P 信号传导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。