ZupT Facilitates Clostridioides difficile Resistance to Host-Mediated Nutritional Immunity.

is a spore-forming bacterium that causes severe colitis and is a major public health threat. During infection, toxin production results in damage to the epithelium and a hyperinflammatory response. The immune response to CDI leads to robust neutrophil infiltration at the sight of infection and the deployment of numerous antimicrobials. One of the most abundant host immune factors associated with CDI is calprotectin, a metal-chelating protein with potent antimicrobial activity. Calprotectin is essential to the innate immune response to and increasing levels of calprotectin correlate with disease severity in both adults and children with CDI. The fact that persists in the presence of high levels of calprotectin suggests that this organism may deploy strategies to compete with this potent antimicrobial factor for essential nutrient metals during infection. In this report, we demonstrate that a putative zinc (Zn) transporter, ZupT, is employed by to survive calprotectin-mediated metal limitation. ZupT is highly expressed in the presence of calprotectin and is required to protect against calprotectin-dependent growth inhibition. When competing against wild-type , mutants show a defect in colonization and persistence in a murine model of infection. Together these data demonstrate that utilizes a metal import system to combat nutritional immunity during CDI and suggest that strategies targeting nutrient acquisition in may have therapeutic potential. During infection, pathogenic organisms must acquire essential transition metals from the host environment. Through the process of nutritional immunity, the host employs numerous strategies to restrict these key nutrients from invading pathogens. In this study, we describe a mechanism by which the important human pathogen resists transition-metal limitation by the host. We report that utilizes a zinc transporter, ZupT, to compete with the host protein calprotectin for nutrient zinc. Inactivation of this transporter in renders this important pathogen sensitive to host-mediated metal restriction and confers a fitness disadvantage during infection. Our study demonstrates that targeting nutrient metal transport proteins in is a potential avenue for therapeutic development.