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Cited by 341Tuberculosis Research and EpidemiologyInfectious Diseases and TuberculosisMycobacterium research and diagnosis

A replication clock for Mycobacterium tuberculosis

Open access
Gill, Wendy P, Harik, Nada S, Whiddon, Molly R, Liao, Reiling P, Mittler, John E, Sherman, David R·2009·Nature Medicine
DOI 10.1038/nm.1915PMC PMC2779834
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Abstract

Few tools exist to assess replication of chronic pathogens during infection. This has been a considerable barrier to understanding latent tuberculosis, and efforts to develop new therapies generally assume that the bacteria are very slowly replicating or nonreplicating during latency. To monitor Mycobacterium tuberculosis replication within hosts, we exploit an unstable plasmid that is lost at a steady, quantifiable rate from dividing cells in the absence of antibiotic selection. By applying a mathematical model, we calculate bacterial growth and death rates during infection of mice. We show that during chronic infection, the cumulative bacterial burden-enumerating total live, dead and removed organisms encountered by the mouse lung-is substantially higher than estimates from colony-forming units. Our data show that M. tuberculosis replicates throughout the course of chronic infection of mice and is restrained by the host immune system. This approach may also shed light on the replication dynamics of other chronic pathogens.

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Crossref · 10.1038/nm.1915

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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 [46]

    The mouse-infection results report continued replication during chronic infection, with a calculated generation time of four days at 16 weeks. The paper does not establish replication during subclinical primate infection; it says the authors plan to study nonhuman primates. Thus it supports the mouse portion, but not the primate portion, of the attributed claim. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • 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 [46]

    The paper reports substantial ongoing M. tuberculosis replication during chronic infection in mice and describes isoniazid as a treatment for latent tuberculosis with virtually no efficacy against nonreplicating bacilli (passages [5] and [1], section labeled Abstract; page unavailable). This supports the reasoning behind the claim, but the paper does not directly measure cell-wall growth or isoniazid effectiveness during chronic infection. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Cites

Flagged first, then by citations

Research works printed but not linked: 30

  1. [1]Warner DF Mizrahi V Tuberculosis chemotherapy: the influence of bacillary stress and damage response pathways on drug efficacy Clin Microbiol Rev 19 558 570 2006 16847086 PMC1539104
  2. [2]Cho SH Low-oxygen-recovery assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosis Antimicrob Agents Chemother 51 1380 1385 2007 17210775 PMC1855511
  3. [3]Lenaerts AJ Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models Antimicrob Agents Chemother 49 2294 2301 2005 15917524 PMC1140539
  4. [4]Frieden TR Sterling TR Munsiff SS Watt CJ Dye C Tuberculosis Lancet 362 887 899 2003 13678977
  5. [5]Wayne LG Sohaskey CD Nonreplicating persistence of Mycobacterium tuberculosis Annu Rev Microbiol 55 139 163 2001 11544352
  6. [6]Harries AD Dye C Tuberculosis Ann Trop Med Parasitol 100 415 431 2006 16899146
  7. [7]Lewis KN Deletion of RD1 from Mycobacterium tuberculosis mimics bacille Calmette-Guerin attenuation J Infect Dis 187 117 123 2003 12508154 PMC1458498
  8. [8]Lazarevic V Nolt D Flynn JL Long-term control of Mycobacterium tuberculosis infection is mediated by dynamic immune responses J Immunol 175 1107 1117 2005 16002712
  9. [9]Rees RJM Hart PD Analysis of the host-parasite equilibrium in chronic murine tuberculosis by total and viable bacillary counts Br J Exp Pathol 42 83 88 1961 13740304 PMC2083177
  10. [10]Munoz-Elias EJ Replication dynamics of Mycobacterium tuberculosis in chronically infected mice Infect Immun 73 546 551 2005 15618194 PMC538940
  11. [11]Cosma CL Humbert O Ramakrishnan L Superinfecting mycobacteria home to established tuberculous granulomas Nat Immunol 5 828 835 2004 15220915
  12. [12]Meijer AH Identification and real-time imaging of a myc-expressing neutrophil population involved in inflammation and mycobacterial granuloma formation in zebrafish Dev Comp Immunol 32 36 49 2008 17553562
  13. [13]Swaim LE Mycobacterium marinum infection of adult zebrafish causes caseating granulomatous tuberculosis and is moderated by adaptive immunity Infect Immun 74 6108 6117 2006 17057088 PMC1695491
  14. [14]Comstock GW Baum C Snider DE Isoniazid prophylaxis among alaskan eskimos: a final report of the Bethel isoniazid studies Am Rev Respir Dis 119 827 830 1979 453704
  15. [15]American Thoracic Society & Centers for Disease Control and Prevention Supplement—American Thoracic Society Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection Am J Respir Crit Care Med 161 S221 S247 2000 10764341
  16. [16]Stover CK A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis Nature 405 962 966 2000 10879539
  17. [17]Kanai K Experimental studies on host-parasite equilibrium in tuberculous infection, in relation to vaccination and chemotherapy Jpn J Med Sci Biol 19 181 199 1966 5297026
  18. [18]Keane J TNF-blocking agents and tuberculosis: new drugs illuminate an old topic Rheumatology (Oxford) 44 714 720 2005 15741198
  19. [19]Bachrach G A new single-copy mycobacterial plasmid, pMF1, from Mycobacterium fortuitum which is compatible with the pAL5000 replicon Microbiology 146 297 303 2000 10708368
  20. [20]Zambrano MM Siegele DA Almiron M Tormo A Kolter R Microbial competition: Escherichia coli mutants that take over stationary phase cultures Science 259 1757 1760 1993 7681219
  21. [21]Smeulders MJ Keer J Speight RA Williams HD Adaptation of Mycobacterium smegmatis to stationary phase J Bacteriol 181 270 283 1999 9864340 PMC103559
  22. [23]Rhoades ER Frank AA Orme IM Progression of chronic pulmonary tuberculosis in mice aerogenically infected with virulent Mycobacterium tuberculosis Tuber Lung Dis 78 57 66 1997 9666963
  23. [24]Mogues T Goodrich ME Ryan L LaCourse R North RJ The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice J Exp Med 193 271 280 2001 11157048 PMC2195922
  24. [25]Rivas-Santiago B β-defensin gene expression during the course of experimental tuberculosis infection J Infect Dis 194 697 701 2006 16897670
  25. [26]Nuermberger E Rifapentine, moxifloxacin or DNA vaccine improves treatment of latent tuberculosis in a mouse model Am J Respir Crit Care Med 172 1452 1456 2005 16151038 PMC1853317
  26. [27]Aly S Oxygen status of lung granulomas in Mycobacterium tuberculosis infected mice J Pathol 210 298 305 2006 17001607
  27. [28]Tsai MC Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension Cell Microbiol 8 218 232 2006 16441433
  28. [29]Via LE Tuberculous granulomas are hypoxic in guinea pigs, rabbits and nonhuman primates Infect Immun 76 2333 2340 2008 18347040 PMC2423064
  29. [30]Wards BJ Collins DM Electroporation at elevated temperatures substantially improves transformation efficiency of slow-growing mycobacteria FEMS Microbiol Lett 145 101 105 1996 8931333
  30. [32]Rustad TR Harrell MI Liao R Sherman DR The enduring hypoxic response of Mycobacterium tuberculosis PLoS ONE 3 e1502 2008 18231589 PMC2198943

Cited by

Sorted by citations

Authors
Gill, W. P., Harik, N. S., Whiddon, M. R., Liao, R. P., Mittler, J. E., & Sherman, D. R.
Affiliations
  • University of Washington Medical Center (US)
  • University of Arkansas for Medical Sciences (US)
  • Center for Infectious Disease Research (US)
  • University of Washington (US)
Corresponding author
Sherman, David R
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2009-02
Volume
15
Issue
2
Pages
211-214
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.1915
PMC
PMC2779834
OpenAlex
W2136913089
Cited by
341
References
2
Citations by year
2026: 11 · 2025: 15 · 2024: 15 · 2023: 14 · 2022: 13 · 2021: 11 · 2020: 19 · 2019: 30 · 2018: 10 · 2017: 26 · 2016: 20 · 2015: 30 · 2014: 27 · 2013: 20 · 2012: 27
FWCI
18.40
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R01AI047744)
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, latent tuberculosis infection, persistent infection, mathematical modeling, bacterial load, host immune control, chronic infection, mouse model
MeSH terms
Animals, Base Sequence, Mice, Inbred C57BL, Mycobacterium tuberculosis, Plasmids, Tuberculosis, Colony Count, Microbial, Polymerase Chain Reaction, DNA Primers, Mice

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