In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D

Dalin Rifat; Victoria L. Campodónico; Jing Tao; James A. Miller; Alpaslan Alp; Yufeng Yao; Petros C. Karakousis

doi:10.2217/fmb-2017-0022

In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D

Dalin Rifat, Victoria L. Campodónico, Jing Tao, James A. Miller, Alpaslan Alp, Yufeng Yao, Petros C. Karakousis

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	753-765
Number of pages	13
Journal	Future microbiology
Volume	12
Issue number	9
DOIs	https://doi.org/10.2217/fmb-2017-0022
State	Published - Jul 2017

Keywords

Mycobacterium tuberculosis
Rpf
inflammation
murine model
nutrient starvation
persistence
progressive hypoxia
resuscitation-promoting factor
rpoB
stringent response
virulence

ASJC Scopus subject areas

Microbiology
Microbiology (medical)

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title = "In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D",

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.",

keywords = "Mycobacterium tuberculosis, Rpf, inflammation, murine model, nutrient starvation, persistence, progressive hypoxia, resuscitation-promoting factor, rpoB, stringent response, virulence",

author = "Dalin Rifat and Campod{\'o}nico, {Victoria L.} and Jing Tao and Miller, {James A.} and Alpaslan Alp and Yufeng Yao and Karakousis, {Petros C.}",

note = "Funding Information: This work was supported by the State Key Development Programs for Basic Research of China (973 program no. 2015CB554203) and the National Natural Science Foundation of China (no. 81361120383) to Y Yao and NIH grant R01AI106613 to PC Karakousis. Publisher Copyright: {\textcopyright} 2017 Future Medicine Ltd.",

year = "2017",

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doi = "10.2217/fmb-2017-0022",

language = "English (US)",

volume = "12",

pages = "753--765",

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T1 - In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D

AU - Rifat, Dalin

AU - Campodónico, Victoria L.

AU - Tao, Jing

AU - Miller, James A.

AU - Alp, Alpaslan

AU - Yao, Yufeng

AU - Karakousis, Petros C.

N1 - Funding Information: This work was supported by the State Key Development Programs for Basic Research of China (973 program no. 2015CB554203) and the National Natural Science Foundation of China (no. 81361120383) to Y Yao and NIH grant R01AI106613 to PC Karakousis. Publisher Copyright: © 2017 Future Medicine Ltd.

PY - 2017/7

Y1 - 2017/7

N2 - 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.

AB - 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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KW - murine model

KW - nutrient starvation

KW - persistence

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KW - resuscitation-promoting factor

KW - rpoB

KW - stringent response

KW - virulence

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In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D

Abstract

Keywords

ASJC Scopus subject areas

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