Cardiomyocyte self-defense against Streptococcus pneumoniae

心肌细胞对抗肺炎链球菌的自我防御

• 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
• 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

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： 四分之一的成年人住院的社区获得性肺炎（CAP）经历了主要不利 心脏事件（狼牙棒）。经历狼牙棒的个人死亡的可能性是那些患者的4-5倍 仅肺炎。帽子的住院也与更大的狼牙棒和心血管相关的风险有关 康复至少5年。因此，肺炎会损害心脏，这与 住院期间和之后，狼牙棒和心血管相关的死亡。肺炎链球菌 （SPN）是一种革兰氏阳性细菌，是CAP和侵入性疾病的主要原因。在侵入性期间 肺炎球菌疾病（IPD），在血液中获得的SPN，可以复制心肌， 杀死心肌细胞和损害功能。值得注意的是，在经过治疗的幸存动物中 抗菌素，由SPN造成的心脏损伤导致组织重塑，具有长期的负面影响 在心脏功能上。因此，心脏中的肺炎球菌是心脏损伤的直接效应者，这有助于 解释与盖相关的狼牙棒。 我们的实验室一直在研究SPN的心肌细胞损伤的分子基础接近 十年。我们做出的一个关键发现是，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。而且，当这些细胞内肺炎球菌持续存在时，它们的复制和 肺炎和过氧化氢的产生导致心肌细胞死亡。因此，我们 选择探讨与LC3相关的吞噬作用的重要性，一种自噬形式 心肌细胞自卫。我们的初步结果支持：1）自噬保护 IPD期间的心； 2）自噬有助于消除心脏中细胞内细菌； 3） 心肌细胞自噬在感染后维持心脏功能。通过测试这些假设通过 以下目的的完成将提高我们对发生的宿主病原体相互作用的理解 在IPD期间的心脏中，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吸收后。这将使用自噬缺陷（ATG7 NULL）成年小鼠在体外进行 心肌细胞和诱导多能干细胞（IPSC）衍生的心肌细胞在新颖的心脏中生长 被SPN感染的组织芯片。 目标2：确定自噬对心脏重塑的影响。这将在体内使用 心肌细胞特异性ATG7无spn感染的无效小鼠。心脏功能将使用 超声心动图使感染后心脏重塑的程度可能与异常相关 功能。