Dalin Rifat1, Victoria L Campodónico1, Jing Tao1,2, James A Miller3, Alpaslan Alp1,4, Yufeng Yao2, Petros C Karakousis1,5. 1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA. 2. Department of Microbiology & Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 3. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA. 4. Department of Medical Microbiology, Hacettepe University Faculty of Medicine, Ankara, Turkey. 5. Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore MD 21205, USA.
Abstract
AIM: 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. MATERIALS & METHODS: 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. RESULTS: 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.
AIM: 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. MATERIALS & METHODS: 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. RESULTS: 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.
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