title: Mycobacterial gene cuvA is required for optimal nutrient utilization and virulence.
abstract: To persist and cause disease in the host, Mycobacterium tuberculosis must adapt to its environment during infection. Adaptations include changes in nutrient utilization and alterations in growth rate. M. tuberculosis Rv1422 is a conserved gene of unknown function that was found in a genetic screen to interact with the mce4 cholesterol uptake locus. The Rv1422 protein is phosphorylated by the M. tuberculosis Ser/Thr kinases PknA and PknB, which regulate cell growth and cell wall synthesis. Bacillus subtilis strains lacking the Rv1422 homologue yvcK grow poorly on several carbon sources, and yvcK is required for proper localization of peptidoglycan synthesis. Here we show that Mycobacterium smegmatis and M. tuberculosis strains lacking Rv1422 have growth defects in minimal medium containing limiting amounts of several different carbon sources. These strains also have morphological abnormalities, including shortened and bulging cells, suggesting a cell wall defect. In both mycobacterial species, the Rv1422 protein localizes uniquely to the growing cell pole, the site of peptidoglycan synthesis in mycobacteria. An M. tuberculosis ΔRv1422 strain is markedly attenuated for virulence in a mouse infection model, where it elicits decreased inflammation in the lungs and shows impaired bacterial persistence. These findings led us to name this gene cuvA (carbon utilization and virulence protein A) and to suggest a model in which deletion of cuvA leads to changes in nutrient uptake and/or metabolism that affect cell wall structure, morphology, and virulence. Its role in virulence suggests that CuvA may be a useful target for novel inhibitors of M. tuberculosis during infection.
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Mir
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sladjana
authors.initials: S
authors.lastname: Prisic
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Choong-Min
authors.initials: CM
authors.lastname: Kang
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shichun
authors.initials: S
authors.lastname: Lun
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Haidan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Murry
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Rubin
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA robert.husson@childrens.harvard.edu.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Husson
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism; D003470:Culture Media / Q000737:chemistry; D004195:Disease Models, Animal; D017353:Gene Deletion; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020102:Mycobacterium smegmatis / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D014376:Tuberculosis / Q000382:microbiology / Q000473:pathology; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D003470:Culture Media; D037521:Virulence Factors; D002244:Carbon