Important Role for Mycobacterium Tuberculosis UvrD1 in Pathogenesis and Persistence Apart from Its Function in Nucleotide Excision Repair

ABSTRACTMycobacterium tuberculosissurvives 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 ofM. tuberculosis. Strains in whichuvrD1was inactivated either alone or in conjunction withuvrAwere constructed. Inactivation ofuvrD1resulted 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). TheuvrD1and theuvrA uvrD1mutants showed decreased intracellular multiplication following infection of macrophages. Most importantly, theuvrA uvrD1mutant was markedly attenuated following infection of mice by either the aerosol or the intravenous route.