DRP1/DMNL-1-mediated mitochondrial fission augments <i>Rickettsia parkeri</i> replication in macrophages

Pathogenic Spotted Fever Group (SFG) <i>Rickettsia</i> species, including <i>Rickettsia parkeri,</i> replicate in endothelial cells and macrophages <i>in vitro</i> and during infections in murine models of disease. We demonstrated that infection of human macrophage-like cells with a related SFG <i>Rickettsia</i>, <i>R. conorii</i>, resulted in a significant increase in mitochondria-associated proteins. However, the role of mitochondrial functions in <i>Rickettsia</i> pathogenesis is unknown. Here, we found that <i>R. parkeri</i> exploits mitochondrial dynamics to promote intracellular replication in mouse and human macrophages by activating the mitochondrial fission regulator, the dynamin-related protein 1 (DRP1). <i>R. parkeri</i> proliferated in macrophages, which coincided with a significant increase in mitochondria fission, mitochondria content, and host cell ATP production, primarily due to mitochondrial respiration compared to uninfected cells. In addition, <i>R. parkeri</i> infection also led to a temporal increase in DRP1 serine phosphorylation that was dependent on rickettsial <i>de novo</i> protein synthesis. Importantly, <i>R. parkeri</i> growth was significantly impacted in DRP1-deficient macrophages. These results suggest that the modulation of mitochondrial fission, content, and function is important for replication and survival of pathogenic SFG <i>Rickettsia</i> species in macrophages. Our data highlight that hijacking mitochondrial dynamics and function is essential for intracellular replication of <i>Rickettsia</i> species and may be a shared mechanism utilized by related obligate intracellular pathogens for growth.