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Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans

Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated muta...

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Autores principales: Colangeli, Roberto, Arcus, Vic L., Cursons, Ray T., Ruthe, Ali, Karalus, Noel, Coley, Kathy, Manning, Shannon D., Kim, Soyeon, Marchiano, Emily, Alland, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949705/
https://www.ncbi.nlm.nih.gov/pubmed/24618815
http://dx.doi.org/10.1371/journal.pone.0091024
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author Colangeli, Roberto
Arcus, Vic L.
Cursons, Ray T.
Ruthe, Ali
Karalus, Noel
Coley, Kathy
Manning, Shannon D.
Kim, Soyeon
Marchiano, Emily
Alland, David
author_facet Colangeli, Roberto
Arcus, Vic L.
Cursons, Ray T.
Ruthe, Ali
Karalus, Noel
Coley, Kathy
Manning, Shannon D.
Kim, Soyeon
Marchiano, Emily
Alland, David
author_sort Colangeli, Roberto
collection PubMed
description Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10(−10) mutations/bp/generation for recently transmitted tuberculosis and 7.3X10(−11) mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10(−11) mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques.
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spelling pubmed-39497052014-03-12 Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans Colangeli, Roberto Arcus, Vic L. Cursons, Ray T. Ruthe, Ali Karalus, Noel Coley, Kathy Manning, Shannon D. Kim, Soyeon Marchiano, Emily Alland, David PLoS One Research Article Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10(−10) mutations/bp/generation for recently transmitted tuberculosis and 7.3X10(−11) mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10(−11) mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques. Public Library of Science 2014-03-11 /pmc/articles/PMC3949705/ /pubmed/24618815 http://dx.doi.org/10.1371/journal.pone.0091024 Text en © 2014 Colangeli et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Colangeli, Roberto
Arcus, Vic L.
Cursons, Ray T.
Ruthe, Ali
Karalus, Noel
Coley, Kathy
Manning, Shannon D.
Kim, Soyeon
Marchiano, Emily
Alland, David
Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans
title Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans
title_full Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans
title_fullStr Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans
title_full_unstemmed Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans
title_short Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans
title_sort whole genome sequencing of mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949705/
https://www.ncbi.nlm.nih.gov/pubmed/24618815
http://dx.doi.org/10.1371/journal.pone.0091024
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