Role of the dosR - dosS Two-Component Regulatory System in Mycobacterium tuberculosis Virulence in Three Animal Models

Abstract

The Mycobacterium tuberculosis dosR gene (Rv3133c) is part of an operon, Rv3134c-Rv3132c, and encodes a response regulator that has been shown to be upregulated by hypoxia and other in vitro stress conditions and may be important for bacterial survival within granulomatous lesions found in tuberculosis. DosR is activated in response to hypoxia and nitric oxide by DosS (Rv3132c) or DosT (Rv2027c). We compared the virulence levels of an M. tuberculosis dosR-dosS deletion mutant (⌬dosR-dosS [⌬dosR-S]), a dosR-complemented strain, and wild-type H37Rv in rabbits, guinea pigs, and mice infected by the aerosol route and in a mouse hollow-fiber model that may mimic in vivo granulomatous conditions. In the mouse and the guinea pig models, the ⌬dosR-S mutant exhibited a growth defect. In the rabbit, the ⌬dosR-S mutant did not replicate more than the wild type. In the hollow-fiber model, the mutant phenotype was not different from that of the wild-type strain. Our analyses reveal that the dosR and dosS genes are required for full virulence and that there may be differences in the patterns of attenuation of this mutant between the animal models studied.

DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions

“…It is within the granuloma that Mtb encounters hypoxia and responds via the induction of the DosR regulon (3). It has been postulated that this regulon is essential for bacterial survival and adaptation during intragranulomatous persistence (4,5), although the data linking DosR to survival or virulence in animals are equivocal (6)(7)(8)(9).…”

“…However, the D-dosR mutant did not exhibit a growthdefect phenotype in C57/Bl6 mice (6). Subsequent studies indicated that D-dosR exhibits reduced growth in rabbit and guinea pig models (8,9). A detailed analysis of the role of the entire DosR regulon in pathogenesis has not been performed in vivo.…”

Differential regulation of the two-component regulatory system senX3-regX3 in Mycobacterium tuberculosis

“…Upon detection of an environmental stimulus, autophosphorylated HK transfers a phosphoryl group to the RR, leading to its activation, which enables DNA binding and initiation of gene transcription, resulting in the appropriate adaptive response (He et al, 2006;Mayuri et al, 2002). Eleven complete pairs of 2CRS and a few isolated HK and RR genes have been identified in the Mtb genome (Cole et al, 1998), several of which have been shown to play an important role in the adaptive responses of the pathogen under stress conditions and in Mtb virulence (Converse et al, 2009;Gonzalo Asensio et al, 2006;Haydel et al, 2012;He et al, 2006;MacArthur et al, 2011;Ohno et al, 2003;Parish et al, 2003).…”

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

“…The EHR is an important component in that it may play a role during the persistent state of infection upon which Mtb remains in a metabolically inactive but viable state. In this vein, DosR and its sensor kinases are required for the pathogenesis of Mtb in nonrodent animal models like rabbits (13), guinea pigs (13,14), and macaques. 3 Pulmonary granulomas in these model systems are known to caseate and develop hypoxia (15).…”