Glutathione Synthesis Regulated by CtrA Protects From Host Cell Oxidative Stress

, a small Gram-negative obligatory intracellular bacterium, infects human monocytes or macrophages, and causes human monocytic ehrlichiosis, one of the most prevalent, life-threatening emerging zoonoses. Reactive oxygen species are produced by the host immune cells in response to bacterial infections. The mechanisms exploited by to resist oxidative stress have not been comprehensively demonstrated. Here, we found that encodes two functional enzymes, GshA and GshB, to synthesize glutathione that confers the oxidative stress resistance, and that the expression of and is upregulated by CtrA, a global transcriptional regulator, upon oxidative stress. We found that in , the expression of and was upregulated upon oxidative stress using quantitative RT-PCR. GshA or GshB restored the ability of GshA or GshB mutant to cope with oxidative stress, respectively. Recombinant CtrA directly bound to the promoters of and , determined with electrophoretic mobility shift assay, and activated the expression of and determined with reporter assay. Peptide nucleic acid transfection of , which reduced the CtrA protein level, inhibited the oxidative stress-induced upregulation of and . Our findings provide insights into the function and regulation of the two enzymes critical for resistance to oxidative stress and may deepen our understanding of pathogenesis and adaptation in hosts.