Regulation of catalase-peroxidase (KatG) expression, isoniazid sensitivity and virulence by furA of Mycobacterium tuberculosis.
Mycobacterium tuberculosis has two genes for ferric uptake regulator orthologues, one of which, furA, is situated immediately upstream of katG encoding catalase-peroxidase, a major virulence factor that also activates the prodrug isoniazid. This association suggested that furA might regulate katG and other genes involved in pathogenesis. Transcript mapping showed katG to be expressed from a strong promoter, with consensus -10 and -35 elements, preceding furA. No promoter activity was demonstrated downstream of the furA start codon, using different gene reporter systems, indicating that furA and katG are co-transcribed from a common regulatory region. The respective roles of these two genes in the isoniazid susceptibility and virulence of M. tuberculosis were assessed by combinatorial complementation of a Delta(furA-katG) strain that is heavily attenuated in a mouse model of tuberculosis. In the absence of furA, katG was upregulated, cells became hypersensitive to isoniazid, and full virulence was restored, indicating that furA regulates the transcription of both genes. When furA alone was introduced into the Delta(furA-katG) mutant, survival in mouse lungs was moderately increased, suggesting that FurA could regulate genes, other than katG, that are involved in pathogenesis. These do not include the oxidative stress genes ahpC and sodA, or those for siderophore production.
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Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 Rue du Dr Roux, 75724 Paris, Cedex 15, France.
Domenech
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Honoré
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N
Song
J
J
Deretic
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V
Cole
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ST
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D004352:Drug Resistance, Microbial / Q000235:genetics; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D005816:Genetic Complementation Test; D007538:Isoniazid / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity*; D009876:Operon; D010544:Peroxidases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D054464:Peroxiredoxins; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D017262:Siderophores / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D014376:Tuberculosis / Q000382:microbiology; D014774:Virulence / Q000235:genetics
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D012097:Repressor Proteins; D017262:Siderophores; C068477:ferric uptake regulating proteins, bacterial; D010544:Peroxidases; D054464:Peroxiredoxins; C076136:catalase HPI; C095500:SodA protein, Bacteria; D013482:Superoxide Dismutase; D007538:Isoniazid