Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

Abstract

Regulating responses to stress is critical for all bacteria, whether they are environmental, commensal, or pathogenic species. For pathogenic bacteria, successful colonization and survival in the host are dependent on adaptation to diverse conditions imposed by the host tissue architecture and the immune response. Once the bacterium senses a hostile environment, it must enact a change in physiology that contributes to the organism's survival strategy. Inappropriate responses have consequences; hence, the execution of the appropriate response is essential for survival of the bacterium in its niche. Stress responses are most often regulated at the level of gene expression and, more specifically, transcription. This minireview focuses on mechanisms of regulating transcription initiation that are required by Mycobacterium tuberculosis to respond to the arsenal of defenses imposed by the host during infection. In particular, we highlight how certain features of M. tuberculosis physiology allow this pathogen to respond swiftly and effectively to host defenses. By enacting highly integrated and coordinated gene expression changes in response to stress, M. tuberculosis is prepared for battle against the host defense and able to persist within the human population.T he survival of any organism relies on its ability to sense and respond to changes in its environment. For bacteria, stress responses are primarily mediated through the regulation of gene expression. By integrating multiple molecular approaches to gene regulation, pathogenic bacteria are able to orchestrate conditionspecific patterns that promote survival and pathogenesis in the face of a strong immune response. This minireview focuses on mechanisms of transcription regulation required for stress responses in one of the most successful and deadly pathogens in the world, Mycobacterium tuberculosis. M. tuberculosis has coexisted with humans for Ͼ50,000 years (1) and continues to cause more than 1.5 million deaths a year (2). The coevolution of M. tuberculosis with the human host response to infection has resulted in a pathogen that is specialized for long-term infection in people. Tuberculosis is a complex disease that requires the bacteria to multiply within phagocytes, survive extracellularly in hypoxic and necrotic granulomas, and endure a robust immune response to persist in the host. During infection, the host immune response restrains M. tuberculosis from proliferating by imposing a battery of defenses, including reactive oxygen and nitrogen stress, hypoxia, acid stress, genotoxic stress, cell surface stress, and starvation (3). Despite this onslaught of attacks, M. tuberculosis is able to persist for the lifetime of the host, indicating that this pathogen has highly effective molecular mechanisms to resist host-inflicted damage. In order to enact these defenses and facilitate this specialized lifestyle, M. tuberculosis executes a complex, interconnected web of stress responses that rely on changes in gene expression. In fact, M. tuberculosis is well suite...

Preexisting variation in DNA damage response predicts the fate of single mycobacteria under stress

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AbmR (Rv1265) is a novel transcription factor of Mycobacterium tuberculosis that regulates host cell association and expression of the non‐coding small RNA Mcr11

“…Bacterial adaptation to the hypoxic environment of a mature granuloma is critical for the persistence of Mtb in non-human primates (Majumdar et al, 2012;Mehra et al, 2015). Mtb's adaptation to host conditions during infection requires gene regulation, so elucidating the gene regulatory networks used by Mtb to sense and respond to host-associated environments may facilitate the design of targeted therapeutics (Shi et al, 2005;Garton et al, 2008;Galagan et al, 2013;Gautam et al, 2015;Banerjee et al, 2016;Du et al, 2016;Flentie et al, 2016;Iona et al, 2016;Sharp et al, 2016).…”

Metabolic Perspectives on Persistence

“…Both prcBA and relA have been reported to facilitate adaptation to in vitro nutrient limitation in M. tuberculosis through roles in amino acid recycling and biosynthesis, respectively. Interestingly, however, expression of a hydrolase null allele of RelA, still competent to synthesize the stringent response alarmone (p)ppGpp, was found to be competent to complement the persistence defect of an isogenic relA -deficient strain in mice (112). Expression of a proteolytically null active site mutant was similarly shown to be sufficient to complement both the in vitro susceptibility to nitric oxide and in vivo persistence defects of prcBA -deficient M. tuberculosis , though complementation of other in vitro persistence defects associated with prolonged stationary phase incubation and nutrient starvation required the wild type allele (107).…”