S. aureus Evades Macrophage Killing through NLRP3-Dependent Effects on Mitochondrial Trafficking
2018
Summary 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.
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