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Cited by 437Tuberculosis Research and EpidemiologyInfectious Diseases and TuberculosisMycobacterium research and diagnosis

Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection

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Ford, Christopher B, Lin, Philana Ling, Chase, Michael R, Shah, Rupal R, Iartchouk, Oleg, Galagan, James, Mohaideen, Nilofar, Ioerger, Thomas R +4 more·2011·Nature Genetics
DOI 10.1038/ng.811PMC PMC3101871
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Abstract

Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance.

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  • M. tuberculosis replicates, albeit slowly, during chronic mouse and subclinical primate infection.

    “M. tuberculosis is thought to replicate, albeit slowly, during chronic mouse and subclinical primate infection46,47; thus, when we refer to 'stasis', we mean that growth and death are in equilibrium, not that growth is arrested.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [47]

    The passage on replication during infection (labeled Abstract; no page given) reports slow replication in mice after ten weeks of chronic infection. For clinically latent primates, it says replication is thought to slow dramatically or cease entirely and that generation time is unknown; it therefore does not establish that slow replication continues in that setting. (LLM, conf=0.83)

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  • Cell wall growth does not completely cease during the chronic phase, so isoniazid does not completely lose its effectiveness.

    “However, cell wall growth does not completely cease during the chronic phase46,47, so isoniazid does not completely lose its effectiveness101.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [47]

    The paper’s discussion of isoniazid preventive therapy for latent infection says that it may selectively kill susceptible bacterial populations, consistent with some retained effectiveness. It presents that killing as a possible explanation, however, and does not establish that isoniazid remains effective during the chronic phase. The preceding cell-wall-growth statement is attributed to other citations, not this paper. (LLM, conf=0.78)

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Cites

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Research works printed but not linked: 27

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Authors
Ford, C. B., Lin, P. L., Chase, M. R., Shah, R. R., Iartchouk, O., Galagan, J., Mohaideen, N., Ioerger, T. R., Sacchettini, J. C., Lipsitch, M., Flynn, J. L., & Fortune, S. M.
Affiliations
  • Harvard University (US)
  • Children's Hospital of Pittsburgh (US)
  • Broad Institute (US)
  • Texas A&M University (US)
  • University of Pittsburgh (US)
Corresponding author
Fortune, Sarah M
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2011-04-24
Volume
43
Issue
5
Pages
482-486
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.811
PMC
PMC3101871
OpenAlex
W2043532115
Cited by
437
References
4
Citations by year
2026: 7 · 2025: 14 · 2024: 29 · 2023: 26 · 2022: 16 · 2021: 15 · 2020: 20 · 2019: 27 · 2018: 29 · 2017: 46 · 2016: 35 · 2015: 41 · 2014: 38 · 2013: 41 · 2012: 42
FWCI
28.18
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL075845, R01HL106804, R33HL092883)
  • National Institute of General Medical Sciences (U54GM088558)
  • National Institute of Allergy and Infectious Diseases (HHSN266200400001C, K08AI063101, U19AI076217, T32AI007638)
  • National Center for Chronic Disease Prevention and Health Promotion (DP2-0D001378)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
  • Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
Keywords
Mycobacterium tuberculosis, mutation rate, latent tuberculosis infection, tuberculosis reactivation, cynomolgus macaques, single nucleotide polymorphisms, oxidative DNA damage, isoniazid resistance, acquired drug resistance
MeSH terms
Animals, Antitubercular Agents, Base Sequence, Disease Models, Animal, DNA, Bacterial, Humans, Isoniazid, Macaca fascicularis, Models, Genetic, Mutation, Mycobacterium tuberculosis, Time Factors, Genome, Bacterial, Tuberculosis, Multidrug-Resistant, Polymorphism, Single Nucleotide, Drug Resistance, Bacterial, Latent Tuberculosis

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