The role of Rel Mtb -mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice
Open accessAbstract
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 (H37RvΔ rel Mtb ) severely compromised in the maintenance of long-term viability. Although aerosol inoculation of mice with H37RvΔ rel 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 H37RvΔ rel Mtb compared with controls throughout the course of the infection. Microarray analysis revealed that H37RvΔ rel 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.
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The transcription of the FAS-I genes fas, accD4 and accD5 seems to correlate with growth.
“The transcrip- tion of the FAS-I genes fas, accD4 and accD5 seems to correlate with growth59,60,88.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [88]
The ‘Virulence factors and cell wall remodeling’ table (page not available) lists fas among genes with higher expression in wild-type bacteria than in the relA mutant. That supports a difference in fas expression, but the paper does not establish that its transcription correlates with growth, and the passages found for accD4 and accD5 do not mention either gene. (LLM, conf=0.76)
Experimental — accuracy not yet measuredmmaA2 and cmaA1, which catalyse the distal cis cyclopropanations on cis/cis-meromycolates, are downregulated by the stress regulator Rel or by starvation.
“mmaA2 and cmaA1, which catalyse the distal cis cyclopropanations on cis/cis- meromycolates, are downregulated by the stress regula- tor Rel88 or by starvation59.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [88]
The table in “Virulence factors and cell wall remodeling” (page unavailable) lists mmaA2 as more highly expressed in the relA mutant, supporting Rel-associated downregulation of mmaA2. The passages do not establish the same effect for cmaA1 or describe either enzyme’s role in distal cis cyclopropanation. The separate starvation citation is not attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThis change is likely partly mediated by the stress regulator Rel, which downregulates fbpA and fbpB and upregulates fbpC.
“This change is likely partly mediated by the stress regulator Rel, which downregulates fbpA and fbpB and upregulates fbpC88.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [88]
In “Virulence factors and cell wall remodeling” (page unavailable), the table lists fbpB as higher in the Rel mutant and fbpC as higher in wild type, supporting the claimed directions for those genes. The discussion says antigen 85A is overexpressed in the mutant, consistent with the fbpA claim, but also says antigen 85C is overexpressed in the mutant—contrary to the table’s fbpC entry. The source is therefore internally inconsistent about fbpC. (LLM, conf=0.78)
Experimental — accuracy not yet measured
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The mycobacterial cell envelope — a moving target
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Are all antibiotic persisters created equal?
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- Authors
- Dahl, J. L., Kraus, C. N., Boshoff, H. I. M., Doan, B., Foley, K., Avarbock, D., Kaplan, G., Mizrahi, V., Rubin, H., & Barry, C. E.
- Affiliations
- National Institute of Allergy and Infectious Diseases (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-08
- Volume
- 100
- Issue
- 17
- Pages
- 10026-10031
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC187750
- OpenAlex
- W2008186432
- Cited by
- 349
- References
- 1
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 11 · 2023: 7 · 2022: 11 · 2021: 15 · 2020: 12 · 2019: 20 · 2018: 15 · 2017: 11 · 2016: 18 · 2015: 20 · 2014: 24 · 2013: 17 · 2012: 15
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI054338, Z01AI000783)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Keywords
- Mycobacterium tuberculosis, stringent response, stationary phase adaptation, long-term persistence, chronic infection, transcriptional regulation, virulence factors, heat shock proteins, cell wall biosynthesis, secreted antigens, immune recognition, latent tuberculosis infection, aerosol infection, Mycobacterium tuberculosis H37Rv
- MeSH terms
- Adaptation, Physiological, Animals, Antigens, Bacterial, Female, Genes, Bacterial, Lung, Mice, Inbred C57BL, Mutation, Mycobacterium tuberculosis, Spleen, Time Factors, Protein Biosynthesis, Tuberculosis, Pulmonary, Tuberculosis, Splenic, Virulence, Colony Count, Microbial, Gene Expression, Gene Deletion, Mice
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