title: Non-replicating Mycobacterium tuberculosis elicits a reduced infectivity profile with corresponding modifications to the cell wall and extracellular matrix.
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.
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Joanna
authors: J
authors: Bacon
authors: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors: Luke J
authors: LJ
authors: Alderwick
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Jon A
authors: JA
authors: Allnutt
authors: MRC Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom.
authors: Evelina
authors: E
authors: Gabasova
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Robert
authors: R
authors: Watson
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Kim A
authors: KA
authors: Hatch
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Simon O
authors: SO
authors: Clark
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Rose E
authors: RE
authors: Jeeves
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Alice
authors: A
authors: Marriott
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Emma
authors: E
authors: Rayner
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Howard
authors: H
authors: Tolley
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Geoff
authors: G
authors: Pearson
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Graham
authors: G
authors: Hall
authors: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors: Gurdyal S
authors: GS
authors: Besra
authors: MRC Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom.
authors: Lorenz
authors: L
authors: Wernisch
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Ann
authors: A
authors: Williams
authors: Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Philip D
authors: PD
authors: Marsh
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics; D000818:Animals; D058491:Bacterial Load / Q000187:drug effects / Q000235:genetics; D002241:Carbohydrates / Q000737:chemistry; D002244:Carbon / Q000494:pharmacology; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006168:Guinea Pigs; D051379:Mice; D058977:Molecular Sequence Annotation; D005810:Multigene Family; D009164:Mycobacterium Infections / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity* / Q000648:ultrastructure; D011136:Polysorbates / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D002241:Carbohydrates; D011136:Polysorbates; D002244:Carbon