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A Mycobacterium marinum mel2 Mutant Is Defective for Growth in Macrophages That Produce Reactive Oxygen and Reactive Nitrogen Species

Department of Microbial and Molecular Pathogenesis, Texas A&M University Health Sciences Center, 471 Reynolds Medical Building, College Station, Texas 77843,¹ Department of Biomedical Sciences, College of Veterinary Medicine, and Department of Microbiology, College of Sciences, Oregon State University, Corvallis, Oregon 97331²

Received 23 June 2006/ Returned for modification 12 September 2006/ Accepted 29 September 2006

Macrophages produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) in response to bacterial infections. Mycobacteria are relatively resistant to ROS, but RNS inhibit growth of, and possibly even kill, mycobacteria in activated macrophages. We recently constructed a Mycobacterium marinum mel2 locus mutant, which is known to affect macrophage infection. We found previously that the mel2 locus confers resistance to ROS and RNS in laboratory medium, suggesting that this locus might play a similar role during growth in macrophages. Since J774A.1 murine macrophages produce high levels of ROS and RNS upon activation with gamma interferon (IFN-), we examined the effects of IFN- on ROS and RNS production by these cells as well as the effects on growth of M. marinum in these cells. We found that an M. marinum mutant with mutation of the first gene in the mel2 locus, melF, is defective for growth in IFN--plus-lipopolysaccharide-treated J774A.1 cells and that this defect is abrogated by the presence of either inhibitors of nitric oxide synthase or ROS scavengers. Furthermore, the M. marinum melF mutant displays a defect at late stages in the mouse footpad model of infection. These phenotypic characteristics could be complemented fully by the entire mel2 locus but only partially by the presence of melF alone, supporting data suggesting that this insertion mutation has polar effects on downstream genes in the mel2 locus. These observations demonstrate that the M. marinum mel2 locus plays a role in resistance to ROS and RNS produced by activated macrophages.

Published ahead of print on 9 October 2006.

Editor: V. J. DiRita

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