Protection ofMycobacterium tuberculosisfrom Reactive Oxygen Species Conferred by themel2Locus Impacts Persistence and Dissemination

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Abstract
Persistence ofMycobacterium tuberculosisin humans represents a major roadblock to elimination of tuberculosis. We describe identification of a locus inM. tuberculosis, mel2, that displays similarity to bacterial bioluminescent loci and plays an important role during persistence in mice. We constructed a deletion of themel2locus and found that the mutant displays increased susceptibility to reactive oxygen species (ROS). Upon infection of mice by aerosol the mutant grows normally until the persistent stage, where it does not persist as well as wild type. Histopathological analyses show that infection with themel2mutant results in reduced pathology and both CFU and histopathology indicate that dissemination of themel2mutant to the spleen is delayed. These data along with growth in activated macrophages and infection of Phox−/−and iNOS−/−mice and bone marrow-derived macrophages suggest that the primary mechanism by whichmel2affects pathogenesis is through its ability to confer resistance to ROS. These studies provide the first insight into the mechanism of action for this novel class of genes that are related to bioluminescence genes. The role ofmel2in resistance to ROS is important for persistence and dissemination ofM. tuberculosisand suggests that homologues in other bacterial species are likely to play a role in pathogenesis.

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