Extracellular vesicles released from Pseudomonas aeruginosa infection causes cardiomyocyte contractile dysfunction 3667

Abstract Description Pseudomonas aeruginosa (P.a.) is a gram negative, opportunistic bacterium, causes severe pneumonia. Surprisingly, up to 30% of patients admitted to the hospital for pneumonia develop adverse cardiovascular complications such as myocardial infarction, arrhythmia, left ventricular dysfunction, and heart. However, the underlying mechanism of infection-mediated heart failure is not yet known. Recently, we demonstrated that P.a. infection of the lungs led to severe cardiacelectircal dysfunction, arrythmia and LV dysfunction with limited dissemination to the heart tissue. To understand the mechanisms of cardiac dysfunction during P.a. infection, we utilized both in vitro and in vivo infection models. Our results revealed that exposure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with conditioned media from P.a. infected human macrophages (hMDMs) causes severe contractile dysfunction in hiPSC-CMs. Specifically, vesicles released from infected hMDMs and bacterial outer membrane vesicles (OMVs) are the major drivers of hiPSC-CMs contractile dysfunction. By using LC-MS/MS, we identified bacterial proteins, including toxins that are packed in the exosomes and OMVs, which are responsible for contractile dysfunction. Additionally, systemic delivery of bacterial OMVs to mice caused severe cardiac dysfunction. In summary, we conclude that OMVs released during infection enter circulation and drive cardiac dysfunction. Funding Sources Funding: NIH-AI46690, AI145262 and AG073720 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)