Significance
The obligate intracellular bacterial pathogen, Coxiella burnetii, is the causative agent of the zoonotic infection termed Q fever. Agricultural outbreaks are an increasingly significant economic and public health burden, and understanding key features of C. burnetii pathogenesis will support the discovery of important targets for future interventions. Significantly, our study has found that a C. burnetii effector protein, MceF (Mitochondrial Coxiella effector protein F), regulates the location of the host protein, GPX4 (Glutathione Peroxidase 4), to protect the host cell from reactive oxygen species–induced cell death. Our findings provide insight into the host–pathogen interactions and demonstrate the utility of studying C. burnetii as a way to gain insight into the programmed cell death of human cells.
Abstract
The causative agent of human Q fever, Coxiella burnetii, 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 C. burnetii and macrophages have limited our knowledge of the mechanisms by which C. burnetii subverts macrophages functions. Here, we used the related bacterium Legionella pneumophila to perform a comprehensive screen of C. burnetii effectors that interfere with innate immune responses and host death using the greater wax moth Galleria mellonella and mouse bone marrow–derived macrophages. We identified MceF (Mitochondrial Coxiella effector protein F), a C. burnetii 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. C. burnetii lacking MceF was replication competent in mammalian cells but induced higher mortality in G. mellonella, indicating that MceF modulates the host response to infection. This study reveals an important C. burnetii 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.
