Heme sensing and detoxification by HatRT contributes to pathogenesis during Clostridium difficile infection.

摘要: Clostridium difficile is a Gram-positive, spore-forming anaerobic bacterium that infects the colon, causing symptoms ranging from infectious diarrhea to fulminant colitis. In last decade, number of C. infections has dramatically risen, making it leading cause reported hospital acquired infection in United States. Bacterial toxins produced during (CDI) damage host epithelial cells, releasing erythrocytes and heme into gastrointestinal lumen. The reactive nature can lead toxicity through membrane disruption, protein lipid oxidation, DNA damage. Here we demonstrate detoxifies excess achieve full virulence within lumen infection, this detoxification occurs heme-responsive expression activated transporter system (HatRT). Heme-dependent transcriptional activation hatRT was discovered an RNA-sequencing analysis grown presence sub-toxic concentration heme. HatRT comprised TetR family regulator (hatR) major facilitator superfamily (hatT). Strains inactivated for hatR or hatT are more sensitive than wild-type. HatR binds heme, which relieves repression operon, whereas HatT functions as efflux pump. murine model CDI, strain displayed lower pathogenicity toxin-independent manner. Taken together, these data suggest senses intracellular concentrations increased operon subsequent by infection. These results describe mechanism employed relieve host, set stage development therapeutic interventions target bacterial-specific system.