The Global Responses of Mycobacterium tuberculosis to Physiological Levels of Copper

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Abstract
Copper (Cu) is a required micronutrient, but it is highly toxic at high concentrations. Therefore, the levels of Cu must be tightly regulated in all living cells. The phagosome of Mycobacterium tuberculosis has been shown to have variable levels of Cu. Previously, we showed that M. tuberculosis contains a copper-sensitive operon, cso , that is induced during early infection in mice. In this study, we showed that ctpV , a gene in the cso operon, is a copper-responsive gene and most likely encodes an efflux pump for Cu. Furthermore, the transcription of key genes in the cso operon is induced by Cu ions and not by other ions, such as Ni and Zn ions. To elucidate copper-responsive genes other than those in the cso operon, we utilized DNA microarrays to profile mycobacterial responses to physiological levels of Cu. A transcriptome analysis identified a novel set of 30 copper-responsive genes in M. tuberculosis , one-half of which were induced only when toxic levels of Cu were added. Interestingly, several transcriptional regulators, including the furA gene, were induced during toxic Cu exposure, indicating that there was a generalized response to oxidative stressors rather than a Cu-specific response. In general, the Cu-induced transcriptome generated should help elucidate the role of the Cu response in maintaining M. tuberculosis survival during infection and could provide novel targets for controlling this virulent pathogen.