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）：幼儿百日咳可进展为复杂和严重的疾病（重症百日咳），通常需要住院治疗，并仍导致惊人的死亡人数。最近的百日咳流行增加了幼儿暴露于感染的可能性，这对接种前婴儿（<2月龄）特别危险。然而，目前还没有治疗重症百日咳的有效疗法。百日咳毒素（PT）是百日咳杆菌的主要毒力因子，其抑制G蛋白信号传导并导致感染婴儿的显著白细胞增多，这是与不良结局相关的发病率。我们假设PT通过对感染和宿主反应的多重影响在重症百日咳的发病机制中起主要作用。我们的初步数据表明，PT促进百日咳感染的致死率在幼年小鼠，但也揭示了百日咳感染和疾病在幼年小鼠有很大的不同，在成年小鼠的特点。这反映了人类的百日咳疾病，婴儿易患严重疾病和死亡，但年龄较大的儿童和成人患的疾病不太严重，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。 可能为百日咳治疗提供治疗潜力的PT宿主靶点是1-磷酸鞘氨醇（S1 P）信号传导，该信号传导由G蛋白偶联受体（GPCR）介导，其信号传导被PT抑制。S1 P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几种细胞过程。在LPS诱导的急性肺损伤和流感病毒感染的小鼠模型中，用S1 P受体激动剂治疗增加肺血管屏障完整性并减少肺部炎症我们已经发现，在细菌接种后不久用S1 P受体激动剂治疗百日咳感染的幼鼠显著降低了这种感染的致死率。因此，我们将研究用S1 P受体激动剂治疗幼鼠百日咳疾病的潜在有益作用，并确定PT抑制S1 P信号传导是否抑制这种有益作用。这项研究可能会发现新的治疗方法来治疗婴儿重症百日咳。