In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D.
There is controversy regarding the potential fitness costs of rifampicin (RIF) resistance-conferring mutations in the Mycobacterium tuberculosis (Mtb) rpoB gene. We characterized the pathogenicity of an Mtb RpoB H526D mutant.



A mutant containing the RpoB H526D mutation was isolated from wild-type Mtb grown on RIF-containing plates and complemented for determination of in vitro and in vivo fitness costs.



The RpoB H526D mutant showed reduced survival relative to control strains during progressive hypoxia and delayed growth following resuscitation from nutrient starvation (p < 0.05), which was associated with reduced expression of the resuscitation-promoting factor genes rpfB, rpfC and rpfE. Relative to the isogenic wild-type strain, the mutant showed significantly attenuated growth and long-term survival as well as reduced inflammation in mouse lungs. Conclusion & future perspective: Our data suggest that RpoB H526D mutation confers a fitness cost during growth-limiting conditions in vitro and in mouse lungs.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA.
Dalin
D
Rifat
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA.
Victoria L
VL
Campodónico
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA.|Department of Microbiology & Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jing
J
Tao
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA.
James A
JA
Miller
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA.|Department of Medical Microbiology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Alpaslan
A
Alp
Department of Microbiology & Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yufeng
Y
Yao
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA.|Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore MD 21205, USA.
Petros C
PC
Karakousis
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics*; D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000235:genetics; D005816:Genetic Complementation Test; D056084:Genetic Fitness; D006801:Humans; D007249:Inflammation; D008168:Lung / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D010100:Oxygen; D060888:Real-Time Polymerase Chain Reaction; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology; D014774:Virulence
D000995:Antitubercular Agents; D001426:Bacterial Proteins; C505805:rpoB protein, Mycobacterium tuberculosis; D012321:DNA-Directed RNA Polymerases; D010100:Oxygen
Mycobacterium tuberculosis; Rpf; inflammation; murine model; nutrient starvation; persistence; progressive hypoxia; resuscitation-promoting factor; rpoB; stringent response; virulence