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.

项目摘要 由百日咳博德特氏菌引起的百日咳是一种重新出现的疾病，引起了重大公共卫生问题。百日咳 严重程度与年龄相关，为B。百日咳引起严重的表现是唯一的幼儿和 在老年时没有观察到。这些婴儿心肺衰竭和死于B的风险增加。 百日咳引起的肺动脉高压（PH）。疾病严重程度的差异表明，宿主 对B的反应。百日咳随年龄而不同。严重百日咳PH的病因机制尚不清楚， 目前还没有有效的治疗方法来治疗与百日咳相关的PH或死亡。 这里提出的研究旨在解决这一关键的知识差距，提供机械信息， 验证百日咳潜在的新疗法的用途。 PH相关的心功能不全是由肺动脉重构引起的，但B. 是百日咳引起的吗为什么这个功能与年龄有关？在未发表的初步研究中， B。发现百日咳可诱导幼鼠肺中的肾素-血管紧张素系统（RAS）活化 而不是成年小鼠，并且B需要百日咳毒素（PT）表达。百日咳诱导的PH。 RAS是高血压发病机制中最重要和研究最多的系统之一， 没有与感染诱导的PH相关。拟议的实验将检验高RAS 婴儿肺中的活性和PT介导的对该系统的保护成分的抑制导致 致病性RAS信号传导并引发导致PH发作的病理。 RAS包括血管紧张素转换酶（ACE）对血管紧张素II（ANGII）的形成和降解 和ACE 2分别与ANGII信号通过AT 1和AT 2受体介导的相反作用， 是致病性的（AT 1，血管收缩和增殖）或保护性的（AT 2，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)B。百日咳可下调成人肺血管紧张素前体基因Agt的表达， 3）B.百日咳在成人肺中下调ACE，但在婴儿肺中不下调; AT 2在婴儿肺中的表达显著高于成人肺。这些数据表明，在婴儿中， 需要高的AT 2水平来限制通过AT 1的过量ANGII信号传导的作用。但是，AT 2，而不是 AT 1对PT介导的抑制敏感，因此感染期间产生的PT将具有更大的影响 对婴儿ANGII信号传导的影响要比成人大。在目标1中，研究了B.百日咳ANGII 检测肽积累和ACE和ACE 2活性。与AT 2相关的表达也将是 测定并测试感染对AT 2活性的影响。在目标2中，RAS的贡献和 PT介导的AT 2对B的抑制。百日咳引起的PH和死亡将得到解决。如果我们假设 正确的，RAS靶向治疗可能会挽救严重百日咳幼儿的生命。

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