A copper uptake ABC transport system is essential forvirulence.

() is a facultative intracellular pathogen that thrives primarily inside the phagosome of macrophages. A keysurvival strategy is to exploit and manipulate metal cation trafficking inside macrophages. Copper plays dual roles in host-pathogen interactions,as a bactericidal toxin for the host, as well as micronutrients for the bacteria. In contrast to the well-studied copper resistance pathways, the copper uptake machinery ofremains poorly characterized. We here show that Rv1273c and Rv1272c form a heterodimeric copper influx ABC transporter in, and their expression is induced by copper and phagocytosis. Intracellular copper imported by Rv1273c-Rv1272c promotes mycobacterial sedimentation and alters bacterial envelope structure. Moreover, copper broadly affects the mycobacterial transcriptome and metabolome, as well as glycolipid and phospholipid contents of the mycobacterial envelope, thereby contributing to mycobacterial survival in macrophages. Finally, the murine model results show that the deletion of Rv1273c-Rv1272c causes lower bacterial burdens in the lungs and spleens, suggesting that Rv1273c-Rv1272c is essential forvirulence. Taken together, these findings demonstrate that mycobacteria utilize the copper uptake ABC transport system to facilitate pathogenesis.