| Mycobacterium tuberculosis, the etiological agent of tuberculosis, infects one-third of the world's population, leading to 1.5 million deaths annually. The success of this pathogen is contingent upon the careful control of numerous regulons to mitigate stress caused by the host's defenses. Among the stress conditions M. tuberculosis faces upon infection are oxidative stress, low pH, hypoxia, and bactericidal levels of copper. This latter condition has recently been characterized, revealing the multifaceted strategy M. tuberculosis employs to combat copper stress.;One of the key copper-responsive operons was originally identified upon induction within the murine model following a low-dose aerosol infection. Members of this operon include ctpV, a copper exporter, and csoR, a copper-sensing transcriptional repressor of its own operon. In this work, we explore the contribution of CsoR in the context of the whole organisms as well as during host infection. M. tuberculosis DeltacsoR survives better than wild type under copper stress, particularly during stationary phase growth, and has an advantage over wild type during the early chronic stages of mouse infection. Despite these advantages, in the absence of csoR, the hypoxia-responsive DosR regulon is induced, suggesting that csoR is important for avoiding respiratory stress and maintaining homeostasis within the cell, even in the absence of high levels of copper.;Further exploration of the response of M. tuberculosis to copper taking advantage of recent advances in sRNA-Seq technology revealed differential expression of 296 sRNAs under both permissive and bactericidal levels of copper. Among these, 224 were discovered in this study, emphasizing the complexity of regulatory networks involved in copper homeostasis.;The same study that identified csoR as responding to host stress, also revealed the induction of two virulence genes, mosR and echA7. Mycobacterium tuberculosis DeltamosR and DeltaechA7 were developed as live attenuated vaccine candidates, and both were found to provide increased protection against an M. tuberculosis Beijing strain challenge compared to that observed with the standard BCG vaccine. Both strains also prime an immune response similar to that of BCG. Overall these two vaccine candidates show promise and will be studied and developed further with the hopes of reaching clinical trials. |
