Enhancement of anti-Group A Streptococcus oxidative burst response in macrophages by polarization 2256833

Introduction Group A Streptococcus (GAS) is a human-specific bacterial pathogen that causes significant mortality during invasive infections. Human macrophages are one of the frontline defenders against GAS infection, limiting bacterial spread through phagocytosis and intracellular pathogen elimination. One mechanism macrophages use to kill bacteria is to produce reactive oxygen species (ROS). Unlike other bacterial species that can use antioxidants or enzymes to neutralize ROS, our data suggests that GAS has a novel ability to prevent ROS production altogether. Since GAS is sensitive to ROS, in this study, we aimed to increase macrophage ROS production by differentiating cells to M1 or M2 subtypes to overcome GAS ROS inhibition. Methods We first confirmed that stimulated, differentiated THP-1 macrophages produce more ROS compared to unstimulated THP-1 monocytes, but that GAS can still effectively repress ROS production. We next found that THP-1 macrophages polarized to the M1 subtype produce more ROS than the M0 and M2 subtypes, and that GAS repression of ROS was less effective in the M1 subtype. ROS production could not be upregulated in the U937 cell line, regardless of polarization. Results At early time points, THP-1 M1 macrophages more effectively eliminated GAS in intracellular killing experiments compared with M0 or M2 polarized THP-1 cells, which corresponded with the ability to produce ROS. Conclusion Overall, our results suggest that upregulation of ROS production by macrophage differentiation can enhance the ability of macrophages to kill GAS, identifying a potential route to target host cells as a treatment for GAS infection.