The role of RelMtb-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 RelMtb and deletion of relMtb produces a strain (H37RvDeltarelMtb) severely compromised in the maintenance of long-term viability. Although aerosol inoculation of mice with H37RvDeltarelMtb 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 H37RvDeltarelMtb compared with controls throughout the course of the infection. Microarray analysis revealed that H37RvDeltarelMtb 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.
Dahl
John L
JL
Tuberculosis Research Section, National Institute of Allergy and Infectious Disease, 12441 Parklawn Drive, Rockville, MD 20852, USA.
Kraus
Carl N
CN
Boshoff
Helena I M
HI
Doan
Bernard
B
Foley
Korrie
K
Avarbock
David
D
Kaplan
Gilla
G
Mizrahi
Valerie
V
Rubin
Harvey
H
Barry
Clifton E
CE
D000222:Adaptation, Physiological; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics; D015169:Colony Count, Microbial; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D005798:Genes, Bacterial; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity* / Q000502:physiology*; D014176:Protein Biosynthesis; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000382:microbiology* / Q000473:pathology; D014400:Tuberculosis, Splenic / Q000382:microbiology* / Q000473:pathology; D014774:Virulence / Q000235:genetics
D000942:Antigens, Bacterial