Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death from an infectious disease worldwide. Over the course of its life cycle in vivo, Mtb is exposed to a plethora of environmental stress conditions. Temporal regulation of genes involved in sensing and responding to such conditions is therefore crucial for Mtb to establish an infection. The Rv2745c (clgR) gene encodes a Clp protease gene regulator that is induced in response to a variety of stress conditions and potentially plays a role in Mtb pathogenesis. Our isogenic mutant, Mtb:ΔRv2745c, is significantly more sensitive to in vitro redox stress generated by diamide, relative to wild-type Mtb as well as to a complemented strain. Together with the fact that the expression of Rv2745c is strongly induced in response to redox stress, these results strongly implicate a role for ClgR in the management of intraphagosomal redox stress. Additionally, we observed that redox stress led to the dysregulation of the expression of the σH/σE regulon in the isogenic mutant, Mtb:ΔRv2745c. Furthermore, induction of clgR in Mtb and Mtb:ΔRv2745c (comp) did not lead to Clp protease induction, indicating that clgR has additional functions that need to be elucidated. Our data, when taken together with that obtained by other groups, indicates that ClgR plays diverse roles in multiple regulatory networks in response to different stress conditions. In addition to redox stress, the expression of Rv2745c correlates with the expression of genes involved in sulfate assimilation as well as in response to hypoxia and reaeration. Clearly, the Mtb Rv2745c-encoded ClgR performs different functions during stress response and is important for the pathogenicity of Mtb in-vivo, regardless of its induction of the Clp proteolytic pathway.
Highlights
One third of the population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) [1]
The ability of Mtb to persist within host tissues for extended period of time indicates that this pathogen has developed unique mechanisms for its survival
A key Mtb stress regulon is controlled by the expression of sigma factors, sH, primarily in response to oxidative stress [16,27]
Summary
One third of the population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) [1]. Infected individuals require a long treatment regimen, ranging from 6 to 12 months that involve serious side effects leading to noncompliance, and the development of resistance. Understanding the interplay between host and pathogen becomes increasingly important in order to develop alternative treatments and more effective vaccines. Residence within the phagolysosome leads to exposure of a plethora of environmental stressors, such as reactive nitrogen species (RNS) and reactive oxygen intermediates (ROI), low pH, and hydrolases, that Mtb must be able to sense and respond to in order to establish an infection [6,7,8,9]. The temporal regulation of genes involved in sensing and responding to environmental stressors becomes increasingly important for understanding the ability of Mtb to take residence within the host MW. Mtb encodes over 200 regulators of transcription including 13 different sigma factors and is well equipped to respond to rapid changes in its environment
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