<i>Coxiella</i> co-opts the Glutathione Peroxidase 4 to protect the host cell from oxidative stress-induced cell death.

Abstract

The causative agent of human Q fever, <i>Coxiella burnetii,</i> is highly adapted to infect alveolar macrophages by inhibiting a range of host responses to infection. Despite the clinical and biological importance of this pathogen, the challenges related to genetic manipulation of both <i>C. burnetii</i> and macrophages have limited our knowledge of the mechanisms by which <i>C. burnetii</i> subverts macrophages functions. Here, we used the related bacterium <i>Legionella pneumophila</i> to perform a comprehensive screen of <i>C. burnetii</i> effectors that interfere with innate immune responses and host death using the greater wax moth <i>Galleria mellonella</i> and mouse bone marrow-derived macrophages. We identified MceF (Mitochondrial Coxiella effector protein F), a <i>C. burnetii</i> effector protein that localizes to mitochondria and contributes to host cell survival. MceF was shown to enhance mitochondrial function, delay membrane damage, and decrease mitochondrial ROS production induced by rotenone. Mechanistically, MceF recruits the host antioxidant protein Glutathione Peroxidase 4 (GPX4) to the mitochondria. The protective functions of MceF were absent in primary macrophages lacking GPX4, while overexpression of MceF in human cells protected against oxidative stress-induced cell death. <i>C. burnetii</i> lacking MceF was replication competent in mammalian cells but induced higher mortality in <i>G. mellonella,</i> indicating that MceF modulates the host response to infection. This study reveals an important <i>C. burnetii</i> strategy to subvert macrophage cell death and host immunity and demonstrates that modulation of the host antioxidant system is a viable strategy to promote the success of intracellular bacteria.