The global redox-responsive transcriptional regulator Rex represses fermentative metabolism and is required forListeria monocytogenespathogenesis
Authors: Halsey Cortney R. , Thomason Maureen K. , Glover Rochelle C. , Reniere Michelle L. 
Published: February 2021

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 that 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 wt. 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.

AUTHOR SUMMARY

Listeriosis is a foodborne illness caused byListeria monocytogenesand is one of the deadliest bacterial infections known, with a mortality rate of up to 30%. Following ingestion of contaminated food,L. monocytogenesdisseminates from the gastrointestinal (GI) tract to peripheral organs, including the spleen, liver, and gallbladder. In this work, we investigated the role of the global redox-responsive regulator Rex inL. monocytogenesgrowth and pathogenesis. We demonstrated that Rex derepression coordinates expression of genes necessary in the GI tract during infection, including fermentative metabolism, bile resistance, and invasion of host cells. Accordingly, Rex was dispensable for colonizing the GI tract of mice during an oral listeriosis infection. Interestingly, Rex-dependent regulation was required for bacterial replication in the spleen, liver, and gallbladder. Taken together, our results demonstrate that Rex-mediated redox sensing and transcriptional regulation are important forL. monocytogenesmetabolic adaptation and virulence.