Pseudomonas aeruginosa Outer Membrane Vesicles (OMVs) Cause Inflammation and Cardiomyocyte Contractile Dysfunction

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Abstract P. aeruginosa (P.a) infection causes severe pneumonia, which can lead to cardiac inflammation and severe cardiac complication. Growing evidence indicates that cardiac resident macrophages are important regulators of inflammation and steady state heart function. On the other hand, pathogen secreted OMVs carry bacterial immunogens that activate the host immune system and alter the homeostasis of normal organ function. Our published results showed that P.a. infection causes cardiac inflammation, fibrosis, and cardiac dysfunction without the bacteria disseminating into heart tissue. However, the mechanism of P.a. induced cardiac inflammation and dysfunction is not known and understanding this is critical for the development of host directed therapy. Thus, we hypothesize that cardiac damage caused by P.a infection is mainly due to the release of bacterial toxins and/or OMVs or by inflammatory mediators released by immune cells. To test our hypothesis we have used human monocyte derived macrophages (hMDMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Our results show that conditioned media from P.a. infected hMDMs causes contractile dysfunction in hiPSC-CMs. In addition, we found that P.a. OMVs induce similar contractile dysfunction in hiPSC-CMs. Notably, we also found that OMV stimulation activates classical inflammatory signaling pathways and enhances hMDM inflammatory cytokine production. These findings demonstrated that P.a OMVs induce inflammatory cytokine production and subsequent myocyte contractile dysfunction. Studies are ongoing to determine the mechanism of OMV induced contractile dysfunction as well as the impact of OMVs on cardiac dysfunction in a mouse model.