Clostridioides difficile Senses and Hijacks Host Heme for Incorporation into an Oxidative Stress Defense System

Clostridioides difficile infection of the colon leads to severe inflammation and damage to the gastrointestinal epithelium due to the production of potent toxins. This inflammatory tissue damage causes the liberation of high concentrations of host heme at infection sites. Here, we identify the C. difficile heme-sensing membrane protein system (HsmRA) and show that this operon induces a protective response that repurposes heme to counteract antimicrobial oxidative stress responses. HsmR senses vertebrate heme, leading to increased expression of the hsmRA operon and subsequent deployment of HsmA to capture heme and reduce redox damage caused by inflammatory mediators of protection and antibiotic therapy. Strains with inactivated hsmR or hsmA have increased sensitivity to redox-active compounds and reduced colonization persistence in a murine model of relapse C. difficile infection. These results define a mechanism exploited by C. difficile to repurpose toxic heme within the inflamed gut as a shield against antimicrobial compounds. [Display omitted] •In the presence of high heme concentrations C. difficile expresses the HsmRA system•HsmA sequesters heme from the host and protects against oxidative stress•The hsmRA operon decreases sensitivity to vancomycin during infection Clostridioides difficile encounters high concentrations of heme at the host-pathogen interface. Knippel et al. discover that the HsmRA system sequesters heme and utilizes the heme bound by the membrane protein HsmA to protect against oxidative stress. The HsmRA system decreases sensitivity to vancomycin in the presence of heme during infection.