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

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), which claims approximately two million people annually, remains a global health concern. The non-replicating or dormancy like state of this pathogen which is impervious to anti-tuberculosis drugs is widely recognized as the culprit for this scenario. The dormancy survival regulator (DosR) regulon, composed of 48 co-regulated genes, is held as essential for Mtb persistence. 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 underlying regulatory mechanism of DosR regulon expression is very complex. Many factors are involved, particularly the oxygen tension. The DosR regulon enables the pathogen to persist during lengthy hypoxia. Comparative genomic analysis demonstrated that the DosR regulon is widely distributed among the mycobacterial genomes, ranging from the pathogenic strains to the environmental strains. In-depth studies on the DosR response should provide insights into its role in TB latency in vivo and shape new measures to combat this exceeding recalcitrant pathogen.

The Mycobacterium tuberculosis Clp Gene Regulator Is Required for in Vitro Reactivation from Hypoxia-induced Dormancy

“…In the isogenic mutant, dosR induction did not occur, whereas at 7 days post-hypoxia levels were ϳ10-fold, indicating that a transition to a vegetative state does occur with Mtb:⌬Rv2745c but does not occur optimally, as dosR expression is needed to transition from a dormant to vegetative state (Fig. 12e) (8). Similar patterns with respect to dosR expression were also found with acr for both Mtb and Mtb: ⌬Rv2745c (Fig.…”

“…For instance, Rv1733c, Rv1738, and Rv2628 are known antigens that have been studied in murine models (8). Specifically, mice infected with Mtb recognize the Rv1733c gene product, which is one of the top ten antigens that is rec- ognized by individuals exposed to Mtb (8).…”

“…7a). Furthermore, DosR regulon antigens are preferentially recognized by T cells of latently infected TB patients and not active TB individuals, implicating that the DosR regulon antigenic profile contributes to host immune pressures that facilitate containment of the bacilli to the granuloma (8). As such, the isogenic mutant has slower activation of the DosR regulon as well as less expression of this regulon.…”

“…Thus, upon increasing oxygen conditions, the transition to a vegetative state was disrupted. Furthermore, it has been shown that expression of dosR is crucial for the optimal shift from a dormant, nonreplicating state to a vegetative state (8). As such, loss of proper dosR signaling and acti- vation of the dosR regulon may contribute to decreased viability of Mtb:⌬Rv2745c.…”

“…Upon low oxygen tension, the pathogen undergoes metabolic changes that facilitate a non-replicating but viable state (1,3,8). Consequently, activation of the DosR regulon leads to dormancy in which there is a shift in the metabolism of Mtb leading to expression of ϳ48 genes within the DosR regulon (11).…”