Circulating Pneumolysin Is a Potent Inducer of Cardiac Injury during Pneumococcal Infection.
Circulating Pneumolysin Is a Potent Inducer of Cardiac Injury during Pneumococcal Infection.
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DOI：
10.1371/journal.ppat.1004836
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发表时间：
2015-05
期刊：
影响因子：
6.7
通讯作者：
Toh CH
中科院分区：
文献类型：
--
作者：
Alhamdi Y;Neill DR;Abrams ST;Malak HA;Yahya R;Barrett-Jolley R;Wang G;Kadioglu A;Toh CH
肺炎链球菌通过包括肺炎、败血症和脑膜炎在内的多种疾病表现，在全球范围内造成的死亡人数超过任何其他单一病原体。与其他细菌感染相比，肺炎球菌感染更常见危及生命的急性心脏并发症。不同的是，尽管有效的抗生素治疗，这些仍然会出现。在这里，我们描述了一种新的机制，心肌损伤，这是触发和持续循环肺炎链球菌溶血素（pneumolysin，Pneumolysin）。使用侵袭性肺炎球菌病（IPD）的小鼠模型，我们证明了野生型PLY表达肺炎球菌，而不是PLY缺陷突变体诱导循环心肌肌钙蛋白（cTns），公认的心脏损伤的生物标志物的升高。此外，升高的cTn水平与肺炎球菌血细胞计数呈线性相关（r=0.688，p=0.001），并且非存活小鼠的cTn水平显著高于存活小鼠。这些cTn水平显着降低PLY螯合脂质体的管理。静脉注射纯化的β-内酰胺酶，而不是非成孔突变体（PdB），诱导心肌肌钙蛋白的大幅增加，表明循环β-内酰胺酶的成孔活性是体内心肌损伤所必需的。纯化的表达P450和PLY的肺炎球菌也引起心肌炎性变化，但未检测到细胞凋亡。培养的心肌细胞暴露于表达PLY的肺炎球菌引起剂量依赖性心肌细胞收缩功能障碍和死亡，抗生素治疗后进一步释放β-内酰胺酶加剧了这种情况。我们发现，高剂量的顺铂诱导广泛的心肌细胞溶解，但更有趣的是，亚溶解性顺铂浓度引发了深刻的钙内流和超载，随后的膜去极化和细胞内钙瞬时振幅的逐步减少，收缩力的关键决定因素。这与临床和实验性脓毒症中通常与心脏功能障碍相关的信号通路的激活相结合，并最终导致心肌细胞收缩性能下降沿着节律紊乱。我们的研究提出了一个详细的肺炎球菌毒素诱导的心脏损伤的分子机制，并强调了主要的翻译潜力，针对循环中的肺炎球菌感染，以防止心脏并发症。心脏并发症经常伴随由病原体肺炎链球菌引起的侵袭性疾病，并与死亡率显著增加相关，但其潜在机制仍不清楚。在这里，我们描述了一种新的机制，通过这种机制，血流中的肺炎球菌诱导循环心肌肌钙蛋白的升高;肌钙蛋白是心脏损伤的标志物，并导致炎性细胞浸润到心肌中。我们证明，这一过程是由循环的肺炎球菌毒素肺炎链球菌溶血素（pneumolysin）介导的。我们还表明，抗生素治疗可以加剧心脏损伤和功能障碍肺炎球菌感染后，由于细菌溶解和释放的β-内酰胺酶，这是一个进一步的机制解释的过程中，心脏瘢痕和炎症。我们证明，除了其在高浓度下诱导心脏细胞死亡的作用外，低浓度（非溶解性）下的钙离子还引发了一系列细胞事件，这些事件始于细胞膜孔形成，大量钙超载，然后介导机械和电干扰心脏细胞的功能。我们的工作提出，新的翻译策略，以检测和中和循环中的肺炎球菌疾病可用于评估疾病的严重程度，并应针对预防/治疗目的。
Streptococcus pneumoniae accounts for more deaths worldwide than any other single pathogen through diverse disease manifestations including pneumonia, sepsis and meningitis. Life-threatening acute cardiac complications are more common in pneumococcal infection compared to other bacterial infections. Distinctively, these arise despite effective antibiotic therapy. Here, we describe a novel mechanism of myocardial injury, which is triggered and sustained by circulating pneumolysin (PLY). Using a mouse model of invasive pneumococcal disease (IPD), we demonstrate that wild type PLY-expressing pneumococci but not PLY-deficient mutants induced elevation of circulating cardiac troponins (cTns), well-recognized biomarkers of cardiac injury. Furthermore, elevated cTn levels linearly correlated with pneumococcal blood counts (r=0.688, p=0.001) and levels were significantly higher in non-surviving than in surviving mice. These cTn levels were significantly reduced by administration of PLY-sequestering liposomes. Intravenous injection of purified PLY, but not a non-pore forming mutant (PdB), induced substantial increase in cardiac troponins to suggest that the pore-forming activity of circulating PLY is essential for myocardial injury in vivo. Purified PLY and PLY-expressing pneumococci also caused myocardial inflammatory changes but apoptosis was not detected. Exposure of cultured cardiomyocytes to PLY-expressing pneumococci caused dose-dependent cardiomyocyte contractile dysfunction and death, which was exacerbated by further PLY release following antibiotic treatment. We found that high PLY doses induced extensive cardiomyocyte lysis, but more interestingly, sub-lytic PLY concentrations triggered profound calcium influx and overload with subsequent membrane depolarization and progressive reduction in intracellular calcium transient amplitude, a key determinant of contractile force. This was coupled to activation of signalling pathways commonly associated with cardiac dysfunction in clinical and experimental sepsis and ultimately resulted in depressed cardiomyocyte contractile performance along with rhythm disturbance. Our study proposes a detailed molecular mechanism of pneumococcal toxin-induced cardiac injury and highlights the major translational potential of targeting circulating PLY to protect against cardiac complications during pneumococcal infections. Cardiac complications frequently accompany invasive disease caused by the pathogen Streptococcus pneumoniae and are associated with significant increases in mortality, however the underlying mechanisms remain elusive. Here, we describe a new mechanism by which pneumococci in the blood stream induce elevation of circulating cardiac troponins; proteins that are markers of cardiac injury and cause inflammatory cell infiltration into the myocardium. We demonstrate that this process is mediated by the circulating pneumococcal toxin pneumolysin (PLY). We also show that antibiotic treatment can exacerbate cardiac injury and dysfunction following pneumococcal infection due to bacterial lysis and the release of PLY, which represents a further mechanistic explanation for the process of cardiac scarring and inflammation. We demonstrate that in addition to its role in inducing death of cardiac cells at high concentrations, PLY at lower (non-lytic) concentrations trigger a range of cellular events starting with cellular membrane pore-formation, substantial calcium overload which then mediates mechanical and electrical disturbance to the function of cardiac cells. Our work proposes that novel translational strategies to detect and neutralize circulating PLY during pneumococcal disease could be utilized to assess disease severity and should be targeted for prevention/treatment purposes.
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