PTEN increases lysosomal acidification and bacterial clearance in macrophages 9319

Abstract Description Macrophages are essential to controlling Staphylococcus aureus infections. The release of antimicrobial effectors, including reactive oxygen (ROS) and nitrogen species (RNI), along with phagolysosome acidification, is vital for killing S. aureus. In this study, we aim to investigate whether the phosphatase PTEN prevents the killing of gram-positive bacteria and to identify the mechanisms involved. Our data indicate that S. aureus activates PTEN and that PTEN-deficient macrophages enhance the killing of S. aureus. We did not observe any impacts on PTEN regarding ROS and RNI. Interestingly, we found increased lysosomal acidification in both naïve and infected PTEN knockout macrophages. RNAseq analysis showed an enrichment of genes associated with responses to S. aureus, phagosome formation, and phagosomal acidification. Additionally, we noted that PTEN deficiency leads to heightened V-ATPase activity. To determine if PTEN-mediated inhibition of phagolysosome acidification affects S. aureus killing, we treated wild-type and PTEN knockout macrophages with the V-ATPase inhibitor bafilomycin A1. Our data demonstrate that the inhibition of V-ATPase reduced the enhanced bacterial killing resulting from PTEN deletion. These findings suggest that PTEN inhibits S. aureus killing by suppressing V-ATPase-dependent phagolysosome acidification. Consequently, we anticipate that inhibiting PTEN could serve as a promising host-targeted therapy for treating antibiotic-resistant S. aureus. Funding Sources Supported by NIH 1R01AI180777-01A1 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)