Group A Streptococcus Induces Lysosomal Dysfunction in THP-1 Macrophages

The human-specific bacterial pathogen Group A Streptococcus (GAS) is a significant cause of morbidity and mortality. Macrophages are important to control GAS upon infection, but previous data indicate that GAS can persist in macrophages. In this study, we detail the molecular mechanisms by which GAS survives in THP-1 macrophages. Our fluorescence microscopy studies demonstrate that GAS are readily phagocytosed by macrophages, but persist within phagolysosomes. These phagolysosomes are not acidified, which is in agreement with the inability of the GAS to survive in low pH environments. We find that the secreted pore-forming toxin Streptolysin O (SLO) perforates the phagolysosomal membrane, allowing leakage of not only protons, but large proteins including the lysosomal protease cathepsin B. Additionally, GAS blocks the activity of vacuolar ATPase (v-ATPase) to prevent acidification of the phagolysosome. Thus, while GAS does not inhibit fusion of the lysosome with the phagosome, it has multiple mechanisms to prevent proper phagolysosome function, allowing for persistence of the bacteria within the macrophage. This has important implications for not only the initial response, but the overall function of the macrophages and resulting pathology in GAS infection and suggests that therapies aimed at improving macrophage function may improve outcomes in GAS infection.