Cardiomyocyte self-defense against Streptococcus pneumoniae

心肌细胞对抗肺炎链球菌的自我防御

基本信息

批准号：
10639102
负责人：
Carlos J Orihuela
金额：
$ 17.97万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-07 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10639102
关键词：
Acute Admission activity Adult Ampicillin Animals Antibodies Arrhythmia Autophagocytosis Bacteria Blood Circulation Cardiac Cardiac Myocytes Cardiovascular system Cell Death Cells Central Nervous System Cessation of life Clathrin Collagen Convalescence Deposition Disease Echocardiography Endocytosis Event Future Gram-Positive Bacteria Heart Heart failure Hospitalization Hour Hydrogen Peroxide Image Impairment In Vitro Incidence Individual Infection Intervention Invaded Knockout Mice Laboratories Lesion Link Mediating Molecular Mus Myocardial Infarction Myocardium Organ Papio Patients Phagocytosis Pneumococcal Infections Pneumonia Production Research Personnel Risk Role Sirius Red F3B Stains Streptococcus pneumoniae Streptococcus pneumoniae plY protein Survivors Testing Time Tissue Microarray Tissue constructs Tissues Troponin antimicrobial capsule cardiac tissue engineering community acquired pneumonia experience heart damage heart function in vivo induced pluripotent stem cell derived cardiomyocytes middle ear mortality novel pathogen resilience uptake

项目摘要

ABSTRACT: One-in-four adults hospitalized for community-acquired pneumonia (CAP) experiences a major adverse cardiac event (MACE). Individuals who experience MACE are 4-5 times more likely to die than those with pneumonia alone. Hospitalization for CAP is also tied to greater risk of MACE and cardiovascular-associated death in convalescence for at least 5 years. Thus, pneumonia damages the heart and this is linked to MACE and cardiovascular-associated death during and after hospitalization. Streptococcus pneumoniae (Spn), a Gram-positive bacterium, is the leading cause of CAP and invasive disease. During invasive pneumococcal disease (IPD), Spn in the bloodstream gains access to the myocardium, where they replicate, kill cardiomyocytes, and impair function. Notably, and in surviving animals that had been treated with antimicrobials, cardiac damage caused by Spn results in tissue remodeling that has long-term negative effects on heart function. Thus, pneumococci in the heart are direct effectors of cardiac damage and this helps to explain CAP-associated MACE. Our laboratory has been studying the molecular basis of cardiomyocyte damage by Spn for close to a decade. One key discovery we have made is that Spn that invade the heart are taken up by cardiomyocytes via clathrin-mediated endocytosis. Moreover, when pneumococci persist within these cells, their replication and production of pneumolysin and hydrogen peroxide results in the death of the cardiomyocyte. Accordingly, we have chosen to explore the importance of LC3-associated phagocytosis, a form of autophagy, on cardiomyocyte self-defense. Our preliminary results support the hypotheses that: 1) autophagy protects the heart during IPD; 2) autophagy contributes to the eradication of intracellular bacteria in the heart; 3) cardiomyocyte autophagy sustains cardiac function post-infection. Testing of these hypotheses via completion of the aims below will advance our understanding of the host-pathogen interactions that take place in the heart during IPD with the potential to influence future intervention strategies. We will: AIM 1: Determine the role of autophagy in protecting cardiomyocyte function and survivability following Spn uptake. This will be done in vitro using autophagy-deficient (ATG7 null) adult mouse cardiomyocytes and induced pluripotent stem cell (iPSC)-derived cardiomyocytes growing in a novel cardiac tissue chip infected with Spn. AIM 2: Determine the impact of autophagy on cardiac remodeling. This will be done in vivo using cardiomyocyte-specific ATG7 null mice infected with Spn. Cardiac function will be evaluated using echocardiography so that the extent of post-infection cardiac remodeling can be correlated to aberrant function.

抽象的：四分之一因社区获得性肺炎 (CAP) 住院的成年人经历过严重不良反应心脏事件（MACE）。经历过 MACE 的人死亡的可能性是患有 MACE 的人的 4-5 倍单独肺炎。 CAP 住院也与 MACE 和心血管相关疾病的风险增加有关康复期死亡至少 5 年。因此，肺炎会损害心脏，这与住院期间和住院后 MACE 和心血管相关死亡。肺炎链球菌 (Spn) 是一种革兰氏阳性细菌，是 CAP 和侵袭性疾病的主要原因。侵入性期间肺炎球菌疾病 (IPD) 中，血液中的 Spn 可以进入心肌并在那里进行复制，杀死心肌细胞，损害功能。值得注意的是，在接受过治疗的幸存动物中抗菌药物中，Spn 引起的心脏损伤会导致组织重塑，从而产生长期负面影响关于心脏功能。因此，心脏中的肺炎球菌是心脏损伤的直接效应物，这有助于解释 CAP 相关的 MACE。我们的实验室近来一直在研究 Spn 对心肌细胞损伤的分子基础。十年。我们的一项重要发现是，侵入心脏的 Spn 被心肌细胞吸收通过网格蛋白介导的内吞作用。此外，当肺炎球菌在这些细胞内持续存在时，它们的复制和肺炎球菌溶血素和过氧化氢的产生导致心肌细胞死亡。据此，我们选择探索 LC3 相关吞噬作用（一种自噬形式）的重要性心肌细胞的自卫能力。我们的初步结果支持以下假设：1）自噬保护 IPD 期间的心脏； 2）自噬有助于消灭心脏内的细胞内细菌； 3）心肌细胞自噬维持感染后的心脏功能。通过以下方式检验这些假设完成以下目标将增进我们对宿主与病原体相互作用的理解 IPD 期间心脏的变化有可能影响未来的干预策略。我们将：目标 1：确定自噬在保护心肌细胞功能和生存能力中的作用 Spn 摄取后。这将使用自噬缺陷（ATG7 null）成年小鼠在体外完成心肌细胞和诱导多能干细胞（iPSC）衍生的心肌细胞在新型心脏中生长感染 Spn 的组织芯片。目标 2：确定自噬对心脏重塑的影响。这将在体内使用感染 Spn 的心肌细胞特异性 ATG7 缺失小鼠。心脏功能将通过以下方式评估超声心动图以便感染后心脏重塑的程度可以与异常相关功能。