title: Carbon flux rerouting during Mycobacterium tuberculosis growth arrest.
abstract: A hallmark of the Mycobacterium tuberculosis life cycle is the pathogen's ability to switch between replicative and non-replicative states in response to host immunity. Transcriptional profiling by qPCR of ∼ 50 M. tuberculosis genes involved in central and lipid metabolism revealed a re-routing of carbon flow associated with bacterial growth arrest during mouse lung infection. Carbon rerouting was marked by a switch from metabolic pathways generating energy and biosynthetic precursors in growing bacilli to pathways for storage compound synthesis during growth arrest. Results of flux balance analysis using an in silico metabolic network were consistent with the transcript abundance data obtained in vivo. Similar transcriptional changes were seen in vitro when M. tuberculosis cultures were treated with bacteriostatic stressors under different nutritional conditions. Thus, altered expression of key metabolic genes reflects growth rate changes rather than changes in substrate availability. A model describing carbon flux rerouting was formulated that (i) provides a coherent interpretation of the adaptation of M. tuberculosis metabolism to immunity-induced stress and (ii) identifies features common to mycobacterial dormancy and stress responses of other organisms.
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Lanbo
authors.initials: L
authors.lastname: Shi
authors.forename: Charles D
authors.initials: CD
authors.lastname: Sohaskey
authors.forename: Carmen
authors.initials: C
authors.lastname: Pheiffer
authors.forename: Carmen
authors.initials: C
authors.lastname: Pfeiffer
authors.forename: Pratik
authors.initials: P
authors.lastname: Datta
authors.forename: Michael
authors.initials: M
authors.lastname: Parks
authors.forename: Johnjoe
authors.initials: J
authors.lastname: McFadden
authors.forename: Robert J
authors.initials: RJ
authors.lastname: North
authors.forename: Maria L
authors.initials: ML
authors.lastname: Gennaro
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002244:Carbon / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008168:Lung / Q000382:microbiology; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D014376:Tuberculosis / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; D002244:Carbon