Abstract
Sepsis induced cardiac dysfunction (SIC) is a severe complication to sepsis which significantly worsens patient outcomes. It is known that bacteria have the capacity to release outer membrane vesicles (OMVs), which are nano-sized bilayered vesicles composed of lipids and proteins, that can induce a fatal inflammatory response. The aim of this study was to determine whether OMVs from a uropathogenic Escherichia coli strain can induce cardiac dysfunction, and to elucidate any mechanisms involved. OMVs induced irregular Ca2+ oscillations with a decreased frequency in cardiomyocytes through recordings of intracellular Ca2+ dynamics. Mice were intraperitoneally injected with bacteria-free OMVs, which resulted in increased concentration of pro-inflammatory cytokine levels in blood. Cytokines were increased in heart lysates, and OMVs could be detected in the heart after OMVs injection. Troponin T was significantly increased in blood, and echocardiography showed increased heart wall thickness as well as increased heart rate. This study shows that E. coli OMVs induce cardiac injury in vitro and in vivo, in the absence of bacteria, and may be a causative microbial signal in SIC. The role of OMVs in clinical disease warrant further studies, as bacterial OMVs in addition to live bacteria may be good therapeutic targets to control sepsis.
Highlights
Sepsis represents a syndrome defined as life-threatening organ dysfunction caused by a dysregulated host response to infection[1]
The outer membrane vesicles (OMVs) isolation completely lacked whole bacteria, as no bacterial structures were observed in transmission electron microscopy (TEM), and attempts to culture bacteria from the OMV isolates in Luria-Bertani broth failed to result in bacterial growth (Supplementary Fig. 1)
We show that OMVs derived from E. coli, without the presence of live bacteria, affect cardiomyocytes in vitro as well as the heart in vivo
Summary
Sepsis represents a syndrome defined as life-threatening organ dysfunction caused by a dysregulated host response to infection[1]. Extensive research over decades suggest that SIC has a complex pathogenesis, and multiple pathways may be involved[2,4]. Both eukaryotic and prokaryotic cells release extracellular vesicles, which are known to mediate intercellular communication[5,6]. It has been shown that OMVs may initiate a sepsis-like inflammatory response, and activate platelets, immune- and endothelial cells to further induce endothelial disruption and a procoagulant state[11,12,13,14]. We isolated OMVs from a uropathogenic Escherichia coli (E. coli) strain and applied these OMVs to cardiomyocytes in vitro, as well as in mice in vivo, quantifying cell or organ function, as well as inflammatory responses. Correspondence and requests for materials should be addressed to J.L.
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