Age-related skewing of angiotensin II signaling potentiates B. pertussis-induced pulmonary hypertension

与年龄相关的血管紧张素 II 信号传导增强百日咳博德特氏菌诱导的肺动脉高压

• 批准号: 10087891
• 负责人: Karen Scanlon
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-24 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087891
• 关键词: ACE2; AGTR2 gene; Address; Adult; Age; Angiotensin II; Angiotensin II Receptor; Angiotensinogen; Angiotensins; Bordetella pertussis; Cardiopulmonary; Catheterization; Cause of Death; Cessation of life; Child; Coupled; Data; Development; Disease; Echocardiography; Etiology; Exposure to; Failure; Fatal Outcome; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genes; Health; Heart; Heart Arrest; Heart failure; Hypertension; Immune response; In Vitro; Infant; Infection; Infectious Agent; Knowledge; Link; Lung; Mediating; Modeling; Mus; Myocardial dysfunction; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peptides; Peptidyl-Dipeptidase A; Pertussis; Pertussis Toxin; Production; Public Health; Pulmonary Hypertension; Pulmonary artery structure; Refractory; Regulation; Renin-Angiotensin System; Research; Right ventricular structure; Risk; Severities; Severity of illness; Signal Transduction; System; Testing; Therapeutic Agents; Therapeutic Intervention; Transcript; Vasodilation; age related; effective therapy; experimental study; improved; in vivo; infant infection; mortality risk; mouse model; novel strategies; novel therapeutics; postnatal; receptor; targeted treatment; therapeutically effective; transcriptome; treatment strategy; vasoconstriction

PROJECT SUMMARY Pertussis, caused by Bordetella pertussis, is a reemerging disease of major public health concern. Pertussis severity is age-related, with B. pertussis causing severe manifestations that are unique to young infants and not observed at an older age. These infants are at increased risk of cardiopulmonary failure and death from B. pertussis-induced pulmonary hypertension (PH). Age-related differences in disease severity indicate that host responses to B. pertussis differ with age. The causal mechanism for PH in severe pertussis is unknown and there are currently no effective therapeutic interventions for the treatment of pertussis-associated PH or death. The study proposed here aims to address this critical gap in knowledge, providing mechanistic information and validating the use of potentially novel therapeutics for pertussis. PH-associated cardiac dysfunction is initiated by remodeling of pulmonary arteries, but how does B. pertussis cause this remodeling? And, why is this function age-related? In unpublished and preliminary studies, B. pertussis was found to induce activation of the renin-angiotensin system (RAS) in the lungs of infant mice but not adult mice and pertussis toxin (PT) expression was required for B. pertussis-induced PH in infant mice. The RAS is one of the most important and best-studies systems in the pathogenesis of hypertension but has not been linked to infection-induced PH. The proposed experiments will test the hypothesis that high RAS activity in the infant lung and PT-mediated inhibition of a protective component of this system cause pathogenic RAS signaling and initiates pathologies that drive the onset of PH. Critical points of regulation in the RAS include the formation and degradation of angiotensin II (ANGII) by angiotensin-converting enzyme (ACE) and ACE2 respectively and ANGII signaling via AT1 and AT2 receptors to mediate opposing actions that may be pathogenic (AT1, vasoconstriction and proliferation) or protective (AT2, vasodilation and anti-proliferative) in our system. Preliminary data also shows that 1) basal pulmonary ANGII levels are higher in infants than adults, 2) B. pertussis downregulates expression of the angiotensin precursor gene Agt in adult lungs but increases expression in infant lungs, 3) B. pertussis downregulates ACE in adult lungs but not infant lungs and 4) basal expression of AT2 is significantly greater in infant lungs than adult lungs. These data indicate that, in infants, high AT2 levels are required to limit the effect of excessive ANGII signaling through AT1. However, AT2, but not AT1, is susceptible to PT-mediated inhibition, hence PT produced during infection would have a greater impact on ANGII signaling in infants than it would in adults. In aim 1, the age-related effect of B. pertussis on ANGII peptide accumulation and ACE and ACE2 activity will be examined. Age-related expression of AT2 will also be determined and the effect of infection of AT2 activity will be tested. In aim 2, the contribution of the RAS and PT-mediated inhibition of AT2 on B. pertussis-induced PH and death will be resolved. If our hypothesis is correct, RAS-targeting therapeutics may save the lives of young infants with severe pertussis.

项目概要 百日咳由百日咳博德特氏菌引起，是一种重新出现的引起重大公共卫生问题的疾病。百日咳 严重程度与年龄有关，百日咳博德特氏菌会引起小婴儿特有的严重症状， 年龄较大时未观察到。这些婴儿发生心肺衰竭和死于双歧杆菌的风险增加。 百日咳引起的肺动脉高压（PH）。疾病严重程度与年龄相关的差异表明宿主 对百日咳博德特氏菌的反应因年龄而异。严重百日咳中 PH 的病因机制尚不清楚， 目前尚无有效的治疗干预措施来治疗百日咳相关的肺动脉高压或死亡。 这里提出的研究旨在解决这一知识上的关键差距，提供机械信息和 验证潜在的百日咳新疗法的使用。 PH 相关的心功能障碍是由肺动脉重塑引发的，但 B. 百日咳会导致这种重塑吗？而且，为什么这个功能与年龄有关？在未发表的初步研究中， 研究发现百日咳博德氏菌可诱导幼鼠肺部肾素-血管紧张素系统 (RAS) 的激活 但成年小鼠不需要，百日咳毒素 (PT) 表达是百日咳博德特氏菌诱导的幼年小鼠 PH 所必需的。 RAS 是高血压发病机制中最重要、研究最好的系统之一，但 与感染引起的 PH 值无关。所提出的实验将检验高 RAS 的假设 婴儿肺中的活性和 PT 介导的对该系统保护性成分的抑制导致 致病性 RAS 信号传导并引发导致 PH 发作的病理。监管关键点 RAS 包括血管紧张素转换酶 (ACE) 形成和降解血管紧张素 II (ANGII) 和 ACE2 分别通过 AT1 和 AT2 受体传递 ANGII 信号，介导可能的相反作用 具有致病性（AT1，血管收缩和增殖）或保护性（AT2，血管舒张和抗增殖） 我们的系统。初步数据还显示，1) 婴儿的基础肺 ANGII 水平高于成人， 2) 百日咳博德特氏菌下调成人肺部血管紧张素前体基因 Agt 的表达，但增加 婴儿肺中的表达，3) 百日咳杆菌下调成人肺中的 ACE，但不下调婴儿肺中的 ACE，4) 基础 AT2在婴儿肺部的表达明显高于成人肺部。这些数据表明，对于婴儿来说， 需要高 AT2 水平来限制通过 AT1 过度 ANGII 信号传导的影响。然而AT2却不是 AT1，容易受到PT介导的抑制，因此感染期间产生的PT会产生更大的影响 婴儿中 ANGII 信号的影响程度高于成人。在目标 1 中，百日咳博德特氏菌对 ANGII 的年龄相关影响 将检查肽积累以及 ACE 和 ACE2 活性。 AT2 的年龄相关表达也将 确定并测试 AT2 活性的感染效果。在目标 2 中，RAS 和 PT 介导的 AT2 对百日咳博德特氏菌诱导的 PH 和死亡的抑制作用将得到解决。如果我们的假设是 正确的 RAS 靶向治疗可能会挽救患有严重百日咳的小婴儿的生命。

项目成果

Pertussis Toxin Promotes Pulmonary Hypertension in an Infant Mouse Model of Bordetella pertussis Infection.

百日咳毒素在百日咳博德特氏菌感染的婴儿小鼠模型中促进肺动脉高压。

• DOI: 10.1093/infdis/jiab325
• 发表时间: 2022
• 期刊: The Journal of infectious diseases
• 作者: Scanlon,KarenM;Chen,Ling;Carbonetti,NicholasH
• 通讯作者: Carbonetti,NicholasH