| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 102 === Streptococcus pyogenes (Group A Streptococcus, GAS) is an important human pathogen and its interaction with blood vessels is critically important in serious events such as bacteremia or multi-organ failure. GAS may internalize into non-phagocytic cells which provide a strategy to escape from immune surveillance and antibiotic killing. However, GAS has also been reported to induce autophagy and is efficiently killed within lysosome-fused autophagosomes in epithelial cells. In the present study, we found that different M serotypes of GAS strains can survive and grow in endothelial cells. The ability of GAS to replicate is related to the clinical symptom severity but not the M serotype. GAS growth causes endothelial cells to undergo a necrotic-like cell death. To investigate the mechanism of insufficient GAS clearance in endothelial cells, we focus on the early stage of infection. Bacterial replication can be suppressed by inactivating GAS in an acidic medium before internalization into endothelial cells, and this inhibitory effect can be reversed by treatment with bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase. As compared with epithelial cells in which acidification causes autophagy-mediated clearance of GAS, there was a defect in acidification of GAS-containing vesicles in endothelial cells. Low pH is consequently not maintained in GAS-containing autophagosomes in endothelial cells, thereby resulting in GAS replication inside LAMP-1 and LC3 positive vesicles. Furthermore, treatment of epithelial cells with bafilomycin A1 resulted in defective GAS clearance by autophagy, with subsequent bacterial growth intracellularly. Taken together, low pH is a key factor for autophagy-mediated suppression of GAS growth inside epithelial cells, while defective acidification of GAS-containing vesicles results in bacterial growth in endothelial cells.
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