Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug resistant tuberculosis

Ford, Christopher B.; Shah, Rupal R.; Maeda, Midori Kato; Gagneux, Sebastien; Murray, Megan B.; Cohen, Ted; Johnston, James C.; Gardy, Jennifer; Lipsitch, Marc; Fortune, Sarah M.

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Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug resistant tuberculosis

Published Date:

Jun 09 2013

Source:

Nat Genet. 45(7):784-790.

[PDF-1.16 MB]

Details:

Personal Authors:

Ford, Christopher B. ; Shah, Rupal R. ; Maeda, Midori Kato ; Gagneux, Sebastien ; Murray, Megan B. ; ... More ▼

Keywords:

[+]

Pubmed ID:

23749189

Pubmed Central ID:

PMC3777616

Description:

A key question in tuberculosis control is why some strains of M. tuberculosis are preferentially associated with resistance to multiple drugs. We demonstrate that M. tuberculosis strains from lineage 2 (East Asian lineage and Beijing sublineage) acquire drug resistances in vitro more rapidly than M. tuberculosis strains from lineage 4 (Euro-American lineage) and that this higher rate can be attributed to a higher mutation rate. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole-genome sequencing of clinical isolates. Finally, using a stochastic mathematical model, we demonstrate that the observed differences in mutation rate predict a substantially higher probability that patients infected with a drug-susceptible lineage 2 strain will harbor multidrug-resistant bacteria at the time of diagnosis. These data suggest that interventions to prevent the emergence of drug-resistant tuberculosis should target bacterial as well as treatment-related risk factors.

Document Type:

Journal Article

Collection(s):

CDC Public Access

Funding:

1 U54 GM088558/GM/NIGMS NIH HHS/United States
DP2 0D001378/DP/NCCDPHP CDC HHS/United States
DP2 OD001378/OD/NIH HHS/United States
T32 AI007638/AI/NIAID NIH HHS/United States
U19 AI076217/AI/NIAID NIH HHS/United States
U19 AI076217/AI/NIAID NIH HHS/United States
U54 GM088558/GM/NIGMS NIH HHS/United States
Howard Hughes Medical Institute/United States

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