S. aureus Evades Macrophage Killing through NLRP3-Dependent Effects on Mitochondrial Trafficking

Clinical severity of Staphylococcus aureus respiratory infection correlates with alpha toxin (AT) expression. AT activates the NLRP3 inflammasome; deletion of Nlrp3, or AT neutralization, protects mice from lethal S. aureus pneumonia. We tested the hypothesis that this protection is not due to a reduction in inflammasome-dependent cytokines (IL-1β/IL-18) but increased bactericidal function of macrophages. In vivo, neutralization of AT or NLRP3 improved bacterial clearance and survival, while blocking IL-1β/IL-18 did not. Primary human monocytes were used in vitro to determine the mechanism through which NLRP3 alters bacterial killing. In cells treated with small interfering RNA (siRNA) targeting NLRP3 or infected with AT-null S. aureus, mitochondria co-localize with bacterial-containing phagosomes. Mitochondrial engagement activates caspase-1, a process dependent on complex II of the electron transport chain, near the phagosome, promoting its acidification. These data demonstrate a mechanism utilized by S. aureus to sequester itself from antimicrobial processes within the cell. [Display omitted] •Alpha toxin activates the inflammasome, preventing bacterial clearance•NLRP3 activation, not downstream cytokine production, leads to impaired defense•Macrophage NLRP3 activation sequesters mitochondria away from internalized S. aureus•Mitochondrial ROS is required for caspase-1 activation and bacterial killing in macrophages In the lung, alpha toxin (AT) is a primary virulence factor used by S. aureus to evade innate immune responses. Cohen et al. demonstrate that AT activation of the NLRP3 inflammasome uncouples key components of the phagocytic killing machinery, namely, mitochondria dissociate from internalized bacteria. Without close association of mitochondria with internalized bacteria, macrophages are unable to effectively kill S. aureus.