Role of the dosR-dosS two-component regulatory system in Mycobacterium tuberculosis virulence in three animal models.
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 (DeltadosR-dosS [DeltadosR-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 DeltadosR-S mutant exhibited a growth defect. In the rabbit, the DeltadosR-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.
Converse
Paul J
PJ
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. pconvers@jhsph.edu
Karakousis
Petros C
PC
Klinkenberg
Lee G
LG
Kesavan
Anup K
AK
Ly
Lan H
LH
Allen
Shannon Sedberry
SS
Grosset
Jacques H
JH
Jain
Sanjay K
SK
Lamichhane
Gyanu
G
Manabe
Yukari C
YC
McMurray
David N
DN
Nuermberger
Eric L
EL
Bishai
William R
WR
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D015964:Gene Expression Regulation, Bacterial; D006168:Guinea Pigs; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000472:pathogenicity*; D009876:Operon / Q000235:genetics; D006656:Protamine Kinase / Q000235:genetics*; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D014376:Tuberculosis / Q000235:genetics* / Q000473:pathology; D014774:Virulence
D001426:Bacterial Proteins; C506260:DevS protein, Mycobacterium tuberculosis; D006656:Protamine Kinase