title: Important role for Mycobacterium tuberculosis UvrD1 in pathogenesis and persistence apart from its function in nucleotide excision repair.
abstract: Mycobacterium tuberculosis survives and replicates in macrophages, where it is exposed to reactive oxygen and nitrogen species that damage DNA. In this study, we investigated the roles of UvrA and UvrD1, thought to be parts of the nucleotide excision repair pathway of M. tuberculosis. Strains in which uvrD1 was inactivated either alone or in conjunction with uvrA were constructed. Inactivation of uvrD1 resulted in a small colony phenotype, although growth in liquid culture was not significantly affected. The sensitivity of the mutant strains to UV irradiation and to mitomycin C highlighted the importance of the targeted genes for nucleotide excision repair. The mutant strains all exhibited heightened susceptibility to representatives of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI). The uvrD1 and the uvrA uvrD1 mutants showed decreased intracellular multiplication following infection of macrophages. Most importantly, the uvrA uvrD1 mutant was markedly attenuated following infection of mice by either the aerosol or the intravenous route.
authors.affiliation: Division of Mycobacterial Research, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom. dillur@nimr.mrc.ac.uk
authors.forename: Joanna
authors.initials: J
authors.lastname: Houghton
authors.forename: Carolin
authors.initials: C
authors.lastname: Townsend
authors.forename: Alan R
authors.initials: AR
authors.lastname: Williams
authors.forename: Angela
authors.initials: A
authors.lastname: Rodgers
authors.forename: Lucinda
authors.initials: L
authors.lastname: Rand
authors.forename: K Barry
authors.initials: KB
authors.lastname: Walker
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
authors.forename: Burkhard
authors.initials: B
authors.lastname: Springer
authors.forename: Elaine O
authors.initials: EO
authors.lastname: Davis
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D014376:Tuberculosis / Q000382:microbiology*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; C573665:UvrD1 protein, Mycobacterium tuberculosis; D004265:DNA Helicases