Hypoxia: a window intoMycobacterium tuberculosislatency

Abstract

SummaryTuberculosis is a massive public health problem on a global scale and the success of Mycobacterium tuberculosis is linked to its ability to persist within humans for long periods without causing any overt disease symptoms. Hypoxia is predicted to be a key host-induced stress limiting growth of the pathogen in vivo. However, multiple studies in vitro and in vivo indicate that M. tuberculosis adapts to oxygen limitation by entering into a metabolically altered state, while awaiting the opportunity to reactivate. Molecular signatures of bacteria adapted to hypoxia in vitro are accumulating, although correlations to human disease are only now being established. Similarly, defining the mechanisms that control this adaptation is an active area of research. In this review we discuss the historical precedents linking hypoxia and latency, and the gathering knowledge of M. tuberculosis hypoxic responses. We also examine the role of these responses in tuberculosis latency, and identify promising avenues for future studies.

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

“…The initial response to hypoxia of MTB includes the altered expression of about 100 genes, including the DosR regulon. The DosR regulon composes of 48 coregulated genes, putatively essential for Mtb survival during latency [Fallow et al, 2010;Rustad et al, 2009], such as the genes involved in alternative electron transport pathways (fdxA), nitrate metabolism (narK2 and narX), triglyceride synthetase (tgs1), and deoxynucleoside triphosphate synthesis under microaerophilic conditions (nrdZ) [Fallow et al, 2010;Rustad et al, 2009]. The DosR regulon is regulated by a two-component regulatory system consisting of two sensor kinases-DosS (Rv3132c) and DosT (Rv2027c), and a response regulator DosR (Rv3133c).…”

“…The C terminus of DosR can bind DNA, and the 54th conserved aspartate is essential for the binding. There is a 20-mer degenerate palindromic motif associating with DosR regulon [Park et al, 2003;Rustad et al, 2009;Vasudeva-Rao and McDonough, 2008]. One variant of this consensus sequence locates upstream of nearly all …”

The photophysics of LOV-based fluorescent proteins — new tools for cell biology

“…This unique property renders them valuable for in vivo applications where molecular oxygen is limited; such as the analysis of microbial pathogenesis, hypoxia induced inflammatory processes, tumor pathophysiology and microbial fermentation as well as for the monitoring and optimization of bioremediation and bacterial production processes (e.g. 15,[16][17][18][19][20][21][22][23][24][25] ). Since the first description in 2007 8 LOV-based FPs were successfully applied in different hypoxic environments 13,14,[26][27][28][29] .…”

Transcription factors Rv0081 and Rv3334 connect the early and the enduring hypoxic response of Mycobacterium tuberculosis

“…Although the exact stimuli that cause M. tb to enter latency are unknown, a variety of studies from human, animals and in vitro conditions point to an intimate link between oxygen tension and the outcome of M. tb infection [5–7,15–17]. For example, M. tb resides within human granulomas during latent infection, which is considered to be a hypoxic environment due to the lack of endothelial and blood vessel markers [18,19].…”

“…For example, M. tb resides within human granulomas during latent infection, which is considered to be a hypoxic environment due to the lack of endothelial and blood vessel markers [18,19]. Conversely, reactivation of LTBI in humans occurs most frequently in the upper lobes of the lungs, which are the most oxygenated regions of the body [7]. …”