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Non-replicating Mycobacterium tuberculosis elicits a reduced infectivity profile with corresponding modifications to the cell wall and extracellular matrix
A key feature of Mycobacterium tuberculosis is its ability to become dormant in the host. Little is known of the mechanisms by which these bacilli are able to persist in this state. Therefore, the focus of this study was to emulate environmental conditions encountered by M. tuberculosis in the granu...
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| Published in: | PloS one 2014-02, Vol.9 (2), p.e87329 |
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| container_issue | 2 |
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| creator | Bacon, Joanna Alderwick, Luke J Allnutt, Jon A Gabasova, Evelina Watson, Robert Hatch, Kim A Clark, Simon O Jeeves, Rose E Marriott, Alice Rayner, Emma Tolley, Howard Pearson, Geoff Hall, Graham Besra, Gurdyal S Wernisch, Lorenz Williams, Ann Marsh, Philip D |
| description | A key feature of Mycobacterium tuberculosis is its ability to become dormant in the host. Little is known of the mechanisms by which these bacilli are able to persist in this state. Therefore, the focus of this study was to emulate environmental conditions encountered by M. tuberculosis in the granuloma, and determine the effect of such conditions on the physiology and infectivity of the organism. Non-replicating persistent (NRP) M. tuberculosis was established by the gradual depletion of nutrients in an oxygen-replete and controlled environment. In contrast to rapidly dividing bacilli, NRP bacteria exhibited a distinct phenotype by accumulating an extracellular matrix rich in free mycolate and lipoglycans, with increased arabinosylation. Microarray studies demonstrated a substantial down-regulation of genes involved in energy metabolism in NRP bacteria. Despite this reduction in metabolic activity, cells were still able to infect guinea pigs, but with a delay in the development of disease when compared to exponential phase bacilli. Using these approaches to investigate the interplay between the changing environment of the host and altered physiology of NRP bacteria, this study sheds new light on the conditions that are pertinent to M. tuberculosis dormancy and how this organism could be establishing latent disease. |
| doi_str_mv | 10.1371/journal.pone.0087329 |
| format | article |
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Little is known of the mechanisms by which these bacilli are able to persist in this state. Therefore, the focus of this study was to emulate environmental conditions encountered by M. tuberculosis in the granuloma, and determine the effect of such conditions on the physiology and infectivity of the organism. Non-replicating persistent (NRP) M. tuberculosis was established by the gradual depletion of nutrients in an oxygen-replete and controlled environment. In contrast to rapidly dividing bacilli, NRP bacteria exhibited a distinct phenotype by accumulating an extracellular matrix rich in free mycolate and lipoglycans, with increased arabinosylation. Microarray studies demonstrated a substantial down-regulation of genes involved in energy metabolism in NRP bacteria. Despite this reduction in metabolic activity, cells were still able to infect guinea pigs, but with a delay in the development of disease when compared to exponential phase bacilli. Using these approaches to investigate the interplay between the changing environment of the host and altered physiology of NRP bacteria, this study sheds new light on the conditions that are pertinent to M. tuberculosis dormancy and how this organism could be establishing latent disease.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0087329</identifier><identifier>PMID: 24516549</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptation ; Adaptation, Physiological - drug effects ; Adaptation, Physiological - genetics ; Animals ; Bacilli ; Bacteria ; Bacterial Load - drug effects ; Bacterial Load - genetics ; Besra ; Biology ; Carbohydrates ; Carbohydrates - chemistry ; Carbon ; Carbon - pharmacology ; Cell Wall - drug effects ; Cell Wall - metabolism ; Cell walls ; Chemistry ; Chromatography, Thin Layer ; Development and progression ; Dormancy ; Electrophoresis, Polyacrylamide Gel ; Energy metabolism ; Environmental conditions ; Extracellular matrix ; Extracellular Matrix - drug effects ; Extracellular Matrix - metabolism ; Fatty acids ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Bacterial - drug effects ; Gene regulation ; Granuloma ; Growth models ; Guinea Pigs ; Hypoxia ; Infections ; Infectivity ; Kinases ; Lipids ; Mathematics ; Medicine ; Metabolism ; Mice ; Molecular Sequence Annotation ; Multigene Family ; Mycobacterium Infections - genetics ; Mycobacterium Infections - microbiology ; Mycobacterium Infections - pathology ; Mycobacterium tuberculosis ; Mycobacterium tuberculosis - genetics ; Mycobacterium tuberculosis - growth & development ; Mycobacterium tuberculosis - pathogenicity ; Mycobacterium tuberculosis - ultrastructure ; Nutrients ; Oxygen ; Physiological aspects ; Physiology ; Polysorbates - pharmacology ; Proteins ; Public health ; Replicating ; Replication ; Studies ; Tuberculosis ; Up-Regulation - genetics</subject><ispartof>PloS one, 2014-02, Vol.9 (2), p.e87329</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Bacon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Bacon et al 2014 Bacon et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-118ab9fb635940b0357405fedf931a84d71e926aebc5328d43e266f238518be93</citedby><cites>FETCH-LOGICAL-c692t-118ab9fb635940b0357405fedf931a84d71e926aebc5328d43e266f238518be93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1495651522/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1495651522?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24516549$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Tyagi, Anil Kumar</contributor><creatorcontrib>Bacon, Joanna</creatorcontrib><creatorcontrib>Alderwick, Luke J</creatorcontrib><creatorcontrib>Allnutt, Jon A</creatorcontrib><creatorcontrib>Gabasova, Evelina</creatorcontrib><creatorcontrib>Watson, Robert</creatorcontrib><creatorcontrib>Hatch, Kim A</creatorcontrib><creatorcontrib>Clark, Simon O</creatorcontrib><creatorcontrib>Jeeves, Rose E</creatorcontrib><creatorcontrib>Marriott, Alice</creatorcontrib><creatorcontrib>Rayner, Emma</creatorcontrib><creatorcontrib>Tolley, Howard</creatorcontrib><creatorcontrib>Pearson, Geoff</creatorcontrib><creatorcontrib>Hall, Graham</creatorcontrib><creatorcontrib>Besra, Gurdyal S</creatorcontrib><creatorcontrib>Wernisch, Lorenz</creatorcontrib><creatorcontrib>Williams, Ann</creatorcontrib><creatorcontrib>Marsh, Philip D</creatorcontrib><title>Non-replicating Mycobacterium tuberculosis elicits a reduced infectivity profile with corresponding modifications to the cell wall and extracellular matrix</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>A key feature of Mycobacterium tuberculosis is its ability to become dormant in the host. Little is known of the mechanisms by which these bacilli are able to persist in this state. Therefore, the focus of this study was to emulate environmental conditions encountered by M. tuberculosis in the granuloma, and determine the effect of such conditions on the physiology and infectivity of the organism. Non-replicating persistent (NRP) M. tuberculosis was established by the gradual depletion of nutrients in an oxygen-replete and controlled environment. In contrast to rapidly dividing bacilli, NRP bacteria exhibited a distinct phenotype by accumulating an extracellular matrix rich in free mycolate and lipoglycans, with increased arabinosylation. Microarray studies demonstrated a substantial down-regulation of genes involved in energy metabolism in NRP bacteria. Despite this reduction in metabolic activity, cells were still able to infect guinea pigs, but with a delay in the development of disease when compared to exponential phase bacilli. 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drug effects</subject><subject>Extracellular Matrix - metabolism</subject><subject>Fatty acids</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Bacterial - drug effects</subject><subject>Gene regulation</subject><subject>Granuloma</subject><subject>Growth models</subject><subject>Guinea Pigs</subject><subject>Hypoxia</subject><subject>Infections</subject><subject>Infectivity</subject><subject>Kinases</subject><subject>Lipids</subject><subject>Mathematics</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Molecular Sequence Annotation</subject><subject>Multigene Family</subject><subject>Mycobacterium Infections - genetics</subject><subject>Mycobacterium Infections - microbiology</subject><subject>Mycobacterium Infections - pathology</subject><subject>Mycobacterium tuberculosis</subject><subject>Mycobacterium tuberculosis - genetics</subject><subject>Mycobacterium tuberculosis - 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Performed the experiments: JB LJA JAA RW KAH SOC AM ER HT GP GH. Analyzed the data: JB LJA JAA EG RW KAH SOC REJ AM ER HT GP GH GSB LW AW PDM. Contributed reagents/materials/analysis tools: LJA EG GSB LW. Wrote the paper: JB LJA JAA EG RW KAH SOC REJ AM ER HT GP GH GSB LW AW PDM.</notes><notes>Competing Interests: Ann Williams is an editor for PLOS one. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. There are no competing interests.</notes><abstract>A key feature of Mycobacterium tuberculosis is its ability to become dormant in the host. Little is known of the mechanisms by which these bacilli are able to persist in this state. Therefore, the focus of this study was to emulate environmental conditions encountered by M. tuberculosis in the granuloma, and determine the effect of such conditions on the physiology and infectivity of the organism. Non-replicating persistent (NRP) M. tuberculosis was established by the gradual depletion of nutrients in an oxygen-replete and controlled environment. In contrast to rapidly dividing bacilli, NRP bacteria exhibited a distinct phenotype by accumulating an extracellular matrix rich in free mycolate and lipoglycans, with increased arabinosylation. Microarray studies demonstrated a substantial down-regulation of genes involved in energy metabolism in NRP bacteria. Despite this reduction in metabolic activity, cells were still able to infect guinea pigs, but with a delay in the development of disease when compared to exponential phase bacilli. Using these approaches to investigate the interplay between the changing environment of the host and altered physiology of NRP bacteria, this study sheds new light on the conditions that are pertinent to M. tuberculosis dormancy and how this organism could be establishing latent disease.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24516549</pmid><doi>10.1371/journal.pone.0087329</doi><tpages>e87329</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-02, Vol.9 (2), p.e87329 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1495651522 |
| source | Publicly Available Content Database; PubMed Central |
| subjects | Adaptation Adaptation, Physiological - drug effects Adaptation, Physiological - genetics Animals Bacilli Bacteria Bacterial Load - drug effects Bacterial Load - genetics Besra Biology Carbohydrates Carbohydrates - chemistry Carbon Carbon - pharmacology Cell Wall - drug effects Cell Wall - metabolism Cell walls Chemistry Chromatography, Thin Layer Development and progression Dormancy Electrophoresis, Polyacrylamide Gel Energy metabolism Environmental conditions Extracellular matrix Extracellular Matrix - drug effects Extracellular Matrix - metabolism Fatty acids Gene expression Gene Expression Profiling Gene Expression Regulation, Bacterial - drug effects Gene regulation Granuloma Growth models Guinea Pigs Hypoxia Infections Infectivity Kinases Lipids Mathematics Medicine Metabolism Mice Molecular Sequence Annotation Multigene Family Mycobacterium Infections - genetics Mycobacterium Infections - microbiology Mycobacterium Infections - pathology Mycobacterium tuberculosis Mycobacterium tuberculosis - genetics Mycobacterium tuberculosis - growth & development Mycobacterium tuberculosis - pathogenicity Mycobacterium tuberculosis - ultrastructure Nutrients Oxygen Physiological aspects Physiology Polysorbates - pharmacology Proteins Public health Replicating Replication Studies Tuberculosis Up-Regulation - genetics |
| title | Non-replicating Mycobacterium tuberculosis elicits a reduced infectivity profile with corresponding modifications to the cell wall and extracellular matrix |
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