Mycobacterium tuberculosis transcriptional adaptation, growth arrest and dormancy phenotype development is triggered by vitamin C.
BACKGROUND
Tubercle bacilli are thought to persist in a dormant state during latent tuberculosis (TB) infection. Although little is known about the host factors that induce and maintain Mycobacterium tuberculosis (M. tb) within latent lesions, O(2) depletion, nutrient limitation and acidification are some of the stresses implicated in bacterial dormancy development/growth arrest. Adaptation to hypoxia and exposure to NO/CO is implemented through the DevRS/DosT two-component system which induces the dormancy regulon.


RESULTS
Here we show that vitamin C (ascorbic acid/AA) can serve as an additional signal to induce the DevR regulon. Physiological levels of AA scavenge O(2) and rapidly induce the DevR regulon at an estimated O(2) saturation of <30%. The kinetics and magnitude of the response suggests an initial involvement of DosT and a sustained DevS-mediated response during bacterial adaptation to increasing hypoxia. In addition to inducing DevR regulon mechanisms, vitamin C induces the expression of selected genes previously shown to be responsive to low pH and oxidative stress, triggers bacterial growth arrest and promotes dormancy phenotype development in M. tb grown in axenic culture and intracellularly in THP-1 cells.


CONCLUSIONS
Vitamin C mimics multiple intracellular stresses and has wide-ranging regulatory effects on gene expression and physiology of M. tb which leads to growth arrest and a 'dormant' drug-tolerant phenotype, but in a manner independent of the DevRS/DosT system. The 'AA-dormancy infection model' offers a potential alternative to other models of non-replicating persistence of M. tb and may be useful for investigating host-'dormant' M. tb interactions. Our findings offer a new perspective on the role of nutritional factors in TB and suggest a possible role for vitamin C in TB.
Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India.
Neetu Kumra
NK
Taneja
Sakshi
S
Dhingra
Aditya
A
Mittal
Mohit
M
Naresh
Jaya Sivaswami
JS
Tyagi
D000222:Adaptation, Physiological / Q000235:genetics*; D000693:Anaerobiosis / Q000187:drug effects; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology*; D002460:Cell Line; D016166:Free Radical Scavengers / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development*; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D018085:Regulon / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
D000975:Antioxidants; D016166:Free Radical Scavengers; D001205:Ascorbic Acid; D010100:Oxygen