The redox-responsive transcriptional regulator Rex represses fermentative metabolism and is required for Listeria monocytogenes pathogenesis

• DOI: 10.1371/journal.ppat.1009379
• Publication Date: 2021-08-16T18:50:57Z
• Authors: Cortney R. Halsey; Rochelle C. Glover; Maureen K. Thomason; Michelle L. Reniere
• Keywords: Mice, Inbred BALB C; 0303 health sciences; Virulence; QH301-705.5; Virulence Factors; Gene Expression Regulation, Bacterial; RC581-607; Listeria monocytogenes; Gene Products, rex; Mice; 03 medical and health sciences; Bacterial Proteins; Fermentation; Animals; Female; Listeriosis; Immunologic diseases. Allergy; Biology (General); Transcriptome; Oxidation-Reduction; Research Article

The Gram-positive bacteriumListeria monocytogenesis the causative agent of the foodborne disease listeriosis, one of the deadliest bacterial infections known. In order to cause disease,L.monocytogenesmust properly coordinate its metabolic and virulence programs in response to rapidly changing environments within the host. However, the mechanisms by whichL.monocytogenessenses and adapts to the many stressors encountered as it transits through the gastrointestinal (GI) tract and disseminates to peripheral organs are not well understood. In this study, we investigated the role of the redox-responsive transcriptional regulator Rex inL.monocytogenesgrowth and pathogenesis. Rex is a conserved canonical transcriptional repressor that monitors the intracellular redox state of the cell by sensing the ratio of reduced and oxidized nicotinamide adenine dinucleotides (NADH and NAD+, respectively). Here, we demonstrated thatL.monocytogenesRex represses fermentative metabolism and is therefore required for optimal growth in the presence of oxygen. We also show thatin vitro, Rex represses the production of virulence factors required for survival and invasion of the GI tract, as a strain lackingrexwas more resistant to acidified bile and invaded host cells better than wild type. Consistent with these results, Rex was dispensable for colonizing the GI tract and disseminating to peripheral organs in an oral listeriosis model of infection. However, Rex-dependent regulation was required for colonizing the spleen and liver, andL.monocytogeneslacking the Rex repressor were nearly sterilized from the gallbladder. Taken together, these results demonstrated that Rex functions as a repressor of fermentative metabolism and suggests a role for Rex-dependent regulation inL.monocytogenespathogenesis. Importantly, the gallbladder is the bacterial reservoir during listeriosis, and our data suggest redox sensing and Rex-dependent regulation are necessary for bacterial survival and replication in this organ.