Regulation of catalase-peroxidase (KatG) expression, isoniazid sensitivityand virulence by furA of Mycobacterium tuberculosis

Mycobacterium tuberculosis has two genes for ferric uptake regulator orthol ogues, one of which, furA, is situated immediately upstream of katG encodin g catalase-peroxidase, a major virulence factor that also activates the pro drug isoniazid, This association suggested that furA might regulate katG an d other genes involved in pathogenesis. Transcript mapping showed katG to b e expressed from a strong promoter, with consensus -10 and -35 elements, pr eceding furA. No promoter activity was demonstrated downstream of the furA start codon, using different gene reporter systems, indicating that furA an d katG are co-transcribed from a common regulatory region, The respective r oles of these two genes in the isoniazid susceptibility and virulence of M. tuberculosis were assessed by combinatorial complementation of a Delta (fu rA-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, end full virulence was restored, indicating that furA regula tes the transcription of both genes. When furA alone was introduced into th e Delta (furA-katG) mutant, survival in mouse lungs was moderately increase d, suggesting that FurA could regulate genes, other than katG, that sie inv olved in pathogenesis. These do not include the oxidative stress genes ahpC and sodA, or those for siderophore production.