Abstract
Mycobacterium tuberculosis can persist for years in the hostile environment of the host in a non-replicating or slowly replicating state. While active disease predominantly results from reactivation of a latent infection, the molecular mechanisms of M. tuberculosis reactivation are still poorly understood. We characterized the physiology and global transcriptomic profiles of M. tuberculosis during reactivation from hypoxia-induced non-replicating persistence. We found that M. tuberculosis reactivation upon reaeration was associated with a lag phase, in which the recovery of cellular physiological and metabolic functions preceded the resumption of cell replication. Enrichment analysis of the transcriptomic dynamics revealed changes to many metabolic pathways and transcription regulons/subnetworks that orchestrated the metabolic and physiological transformation in preparation for cell division. In particular, we found that M. tuberculosis reaeration lag phase is associated with down-regulation of persistence-associated regulons/subnetworks, including DosR, MprA, SigH, SigE, and ClgR, as well as metabolic pathways including those involved in the uptake of lipids and their catabolism. More importantly, we identified a number of up-regulated transcription regulons and metabolic pathways, including those involved in metal transport and remobilization, second messenger-mediated responses, DNA repair and recombination, and synthesis of major cell wall components. We also found that inactivation of the major alternative sigma factors SigE or SigH disrupted exit from persistence, underscoring the importance of the global transcriptional reprogramming during M. tuberculosis reactivation. Our observations suggest that M. tuberculosis lag phase is associated with a global gene expression reprogramming that defines the initiation of a reactivation process.
Highlights
Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis, became the top deadly infectious disease, responsible for the death of about 1.5 million people in 2014 (WHO, 2015)
Our findings suggest that M. tuberculosis reactivation is a programmed exit from persistence, which requires a coordinated change of gene expression in various regulatory and metabolic pathways
M. tuberculosis is gradually depleted of oxygen, whereby after 3 days of replication the bacilli enter into a non-replicating persistent state and they are in full anaerobiosis after 9 days (Wayne and Hayes, 1996)
Summary
Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis, became the top deadly infectious disease, responsible for the death of about 1.5 million people in 2014 (WHO, 2015). Mechanism of TB Reactivation to exist within host granulomas in a non-replicating persistent state with low metabolic activity (Hobby et al, 1954; Wayne and Sohaskey, 2001; Dutta and Karakousis, 2014). This special physiological state of M. tuberculosis accounts for the successful evasion from the host immunity as well as the long duration of treatment regimen with anti-tuberculosis drugs, which leads to increased cases of toxicity and low rates of treatment completion (Hobby et al, 1954; Dutta and Karakousis, 2014; Muñoz et al, 2015; Turetz and Ma, 2016). Given the fact that the major cause of morbidity and mortality from tuberculosis results predominantly from reactivation of an undiagnosed latent infection (WHO, 2015), a better understanding of reactivation biology may yield novel assays that can identify persons at highest risk for progression to clinical disease, and novel therapeutic strategies to shorten the treatment of latent M. tuberculosis infection
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