Inhibition of Respiration by Nitric Oxide Induces a Mycobacterium tuberculosis Dormancy Program
By M. Voskuil, D. Schnappinger, Kevin C. Visconti, M. Harrell, G. Dolganov, David R. Sherman, G. Schoolnik. Journal of Experimental Medicine, 2003
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An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis.
Subfields: Epidemiology, Infectious Diseases, Molecular Medicine
View Paper: https://www.semanticscholar.org/paper/b0919257eed204e4cf30d57e55717623e79cf34f
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Citations in the corpus
- Foamy Macrophages from Tuberculous Patients' Granulomas Constitute a Nutrient-Rich Reservoir for M. tuberculosis Persistence (2008, methodology): “For this purpose, we analyzed the expression of a series of genes known to be up-regulated when bacilli are in a persistent non-replicating state [23,24].”
- Antimicrobial reactive oxygen and nitrogen species: concepts and controversies (2004, background): “RNS might have a particularly important role in the maintenance of latent infection”
- High Functional Diversity in Mycobacterium tuberculosis Driven by Genetic Drift and Human Demography (2008, background): “These 89 genes comprised housekeeping genes and antigens analyzed in the early sequencing studies mentioned above [14,15], as well as genes of special interest, including putative new drug targets [29–31], genes believed to be involved in latency and reactivation [32,33], DNA repair genes [34], gene”
- The spectrum of latent tuberculosis: rethinking the goals of prophylaxis (2009, positive): “For example, the two-component response regulator DosR, which is controlled by the sensor kinases–DosS and DosT and is central to hypoxic adaptation, is also upregulated by exposure to nitric oxid”