Abstract
Research on toxin-antitoxin loci (TA loci) is gaining impetus due to their ubiquitous presence in bacterial genomes and their observed roles in stress survival, persistence and drug tolerance. The present study investigates the expression profile of all the seventy-nine TA loci found in Mycobacterium tuberculosis. The bacterium was subjected to multiple stress conditions to identify key players of cellular stress response and elucidate a TA-coexpression network. This study provides direct experimental evidence for transcriptional activation of each of the seventy-nine TA loci following mycobacterial exposure to growth-limiting environments clearly establishing TA loci as stress-responsive modules in M. tuberculosis. TA locus activation was found to be stress-specific with multiple loci activated in a duration-based response to a particular stress. Conditions resulting in arrest of cellular translation led to greater up-regulation of TA genes suggesting that TA loci have a primary role in arresting translation in the cell. Our study identifed higBA2 and vapBC46 as key loci that were activated in all the conditions tested. Besides, relBE1, higBA3, vapBC35, vapBC22 and higBA1 were also upregulated in multpile stresses. Certain TA modules exhibited co-activation across multiple conditions suggestive of a common regulatory mechanism.
Highlights
Research on toxin-antitoxin loci (TA loci) is gaining impetus due to their ubiquitous presence in bacterial genomes and their observed roles in stress survival, persistence and drug tolerance
Considering the fact that M. tuberculosis harbors an unusually high number of TA loci for any bacterial genome and more importantly, significantly higher than other closely related mycobacteria like M. avium, M. bovis and M. smegmatis, it will be useful to analyze the expression profiles of TA genes under different stress conditions thought to mimic the host environment during mycobacterial infection to elucidate their contribution towards the survival ability of this deadly pathogen
TA loci identified in various bacterial genomes are grouped into families based on sequence homology and biochemical properties[26]
Summary
Research on toxin-antitoxin loci (TA loci) is gaining impetus due to their ubiquitous presence in bacterial genomes and their observed roles in stress survival, persistence and drug tolerance. TA-encoded toxins act to rapidly slow down cellular processes, giving bacteria an opportunity to alter their metabolic program and enter into a dormant or non-replicating state and exhibit a persistent or drug-tolerant phenotype[4,6,7,20,21,22]. Considering the fact that M. tuberculosis harbors an unusually high number of TA loci for any bacterial genome and more importantly, significantly higher than other closely related mycobacteria like M. avium, M. bovis and M. smegmatis, it will be useful to analyze the expression profiles of TA genes under different stress conditions thought to mimic the host environment during mycobacterial infection to elucidate their contribution towards the survival ability of this deadly pathogen. A system-wide screening will help identify specific TA loci differentially expressed under different growth conditions and shed light on co-regulated pathways/genes that could provide clues to mechanisms for TA activation and regulation
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