The role of Rel_Mtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice

Long-term survival of nonreplicating Mycobacterium tuberculosis (Mtb) is ensured by the coordinated shutdown of active metabolism through a broad transcriptional program called the stringent response. In Mtb, this response is initiated by the enzymatic action of Rel_Mtb and deletion of rel _Mtb produces a strain (H37RvΔrel_Mtb) severely compromised in the maintenance of long-term viability. Although aerosol inoculation of mice with H37RvΔrel_Mtb results in normal initial bacterial growth and containment, the ability of this strain to sustain chronic infection is severely impaired. Significant histopathologic differences were noted in lungs and spleens of mice infected with H37RvΔrel _Mtb compared with controls throughout the course of the infection. Microarray analysis revealed that H37RvΔrel_Mtb suffers from a generalized alteration of the transcriptional apparatus, as well as specific changes in the expression of virulence factors, cell-wall biosynthetic enzymes, heat shock proteins, and secreted antigens that may alter immune recognition of the recombinant organism. Thus, Rel_Mtb is critical for the successful establishment of persistent infection in mice by altering the expression of antigenic and enzymatic factors that may contribute to successful latent infection.