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.

摘要： 四分之一的因社区获得性肺炎（CAP）住院的成年人经历了严重的不良反应， 心脏事件（MACE）。发生MACE的个体死亡的可能性是发生MACE的个体的4-5倍。 只有肺炎。CAP的住院治疗也与MACE和心血管相关性心血管事件的风险增加有关。 在康复期死亡至少5年。因此，肺炎损害心脏，这与 住院期间和住院后的MACE和心血管相关死亡。肺炎链球菌 (Spn)是一种革兰氏阳性菌，是CAP和侵袭性疾病的主要原因。在侵入性 肺炎球菌病（IPD）时，血流中的Spn进入心肌，在那里复制， 杀死心肌细胞并损害功能。值得注意的是，在接受过 抗微生物剂，由Spn引起的心脏损伤导致具有长期负面影响的组织重塑 对心脏功能的影响因此，心脏中的肺炎球菌是心脏损伤的直接效应物， 以解释CAP相关MACE。 我们的实验室已经研究了近一年来Spn对心肌细胞损伤的分子基础。 十年我们的一个关键发现是，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。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。因此我们 选择探索LC 3相关吞噬作用的重要性，这是一种自噬形式， 心肌细胞自我防御我们的初步研究结果支持以下假设：1）自噬保护了 IPD期间的心脏; 2）自噬有助于根除心脏中的细胞内细菌; 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 完成以下目标将促进我们对宿主-病原体相互作用的理解 在IPD期间心脏中存在潜在影响未来干预策略的风险。我们将： 目的1：确定自噬在保护心肌细胞功能和存活能力中的作用 在Spn摄取之后。这将在体外使用自噬缺陷型（ATG 7缺失型）成年小鼠进行 心肌细胞和诱导多能干细胞（iPSC）衍生的心肌细胞在一种新的心脏 感染了Spn的组织芯片 目的2：确定自噬对心脏重构的影响。这将在体内使用 感染Spn的心肌细胞特异性ATG 7缺失小鼠。将使用以下指标评价心脏功能 超声心动图，以便感染后心脏重塑的程度可以与异常的 功能