The mechanism behind inefficient group A streptococcus clearance by autophagy in endothelial cells: defective acidification of bacteria-containing autophagosomes

Abstract

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

Date of Award	2014 Aug 26
Original language	English
Supervisor	Yee-Shin Lin (Supervisor)