Mechanisms of Innate Immune Response Activation in Human Monocytes by Small Extracellular Vesicles Released During Infection with Burkholderia thailandensis
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The function of small extracellular vesicles (sEVs) released from host cells during bacterial infections is still largely uncharacterized, despite EVs representing key components of cell-to-cell communication. In particular, there is still a strong gap in knowledge about sEV released from innate immune cells that are infected with high-consequence pathogens such Burkholderia pseudomallei (Bp), including the molecular mechanisms by which these host-derived vesicles alter innate immune cell function. The Hakami laboratory had previously demonstrated that sEV released from monocytes that are infected with the Bp model organism Burkholderia thailandensis (EXi-Bt) induce specific phenotypic changes within naïve recipient monocytes. Specifically, they cause differentiation of the monocytes to macrophage-like cells, increased production of pro-inflammatory cytokines, and reduced intracellular bacterial burden if the cells are infected post sEV treatment. In this work, we have characterized the signaling pathways and cellular processes involved in these observed EXi-Bt-associated phenotypes. We demonstrate that the p38 MAP kinase pathway is involved for several of the observed effects, with chemical inhibition of p38 activity resulting in phenotype loss within EXi-Bt-treated cells. We also show that while IL-6 production is important for the reduced bacterial burden phenotype, it does not impact the monocyte-to-macrophage differentiation effect. Importantly, we show that EXi-Bt induces autophagy within the macrophage-like cell population, and that inhibition of autophagy by siRNA knockdown of Atg5 leads to a reversal of the reduced bacterial burden phenotype within the EXi-Bt-treated cells. These findings suggest that sEV released from Bt-infected monocytic cells prime recipient cells for enhanced response to bacterial challenge via the p38 and IL-6 signaling pathways and through induction of autophagy. The mechanistic characterization of these EXi-Bt-induced phenotypes provides further insight into the innate immune response that occurs during Bp infection, which may help inform the development of novel preventative and therapeutic strategies.