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

John L. Dahl, Carl N. Kraus, Helena I.M. Boshoff, Bernard Doan, Korrie Foley, David Avarbock, Gilla Kaplan, Valerie Mizrahi, Harvey Rubin, Clifton E. Barry

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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 RelMtb and deletion of rel Mtb produces a strain (H37RvΔrelMtb) severely compromised in the maintenance of long-term viability. Although aerosol inoculation of mice with H37RvΔrelMtb 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 H37RvΔrelMtb 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, RelMtb 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.

Original languageEnglish (US)
Pages (from-to)10026-10031
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Aug 19 2003

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