Brucella rough RB51 infection activates P53-Slc7a11-Gpx4/GSH pathway to induce ferroptosis to attenuate the intracellular survival on macrophages.

B. abortus is a facultative intracellular bacterium that replicates within macrophages. Intracellular survival is one of the important indexes to evaluate the virulence of Brucella. Ferroptosis is a type of programmed cell death induced by the accumulation of free iron, reactive oxygen species (ROS), and toxic lipid peroxides, play roles on cancers, cardiovascular diseases, and inflammatory diseases. In this study, we found that Brucella rough strain RB51 induced ferroptosis on macrophages with reduced levels of host glutathione and glutathione peroxidase 4 (Gpx4), together with increased ferrous iron, lipid peroxidation, and ROS. The inhibitor ferrostatin-1 significantly reduced the ferroptosis of RB51-infected macrophages, confirming that ferroptosis occurred during infection with Brucella RB51. Furthermore, we found that RB51 infection induced ferroptosis is regulated by P53-Slc7a11-Gpx4/GSH signal pathway. Inhibiting P53 decreased the levels of ROS and lipid peroxidation, while the levels of Slc7a11, Gpx4 and GSH were rescued. More importantly, inhibiting ferroptosis by different ferroptosis inhibitors increased the intracellular survival of Brucella RB51, indicating ferroptosis functions on the attenuation of Brucella intracellular survival. Collectively, our observations demonstrate that Brucella RB51 infection induces ferroptosis on macrophages, which is regulated by P53-Slc7a11-Gpx4/GSH signal pathway and functions on the attenuation of intracellular survival of Brucella.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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