Identification of two Mycobacterium marinum loci that affect interactions with macrophages

Mycobacterium marinum is closely related to Mycobacterium tuberculosis, the cause of tuberculosis in humans. M. marinum has become an important model system for the study of the molecular mechanisms involved in causing tuberculosis in humans. Through molecular genetic analysis of the differences between pathogenic and nonpathogenic mycobacteria, we identified two loci that affect the ability of M. marinum to infect macrophages, designated mel(1) and mel(2). In silico analyses of the 11 putative genes in these loci suggest that mel(1) encodes secreted proteins that include a putative membrane protein and two putative transglutaminases, whereas mel(2) is involved in secondary metabolism or biosynthesis of fatty acids. Interestingly, mel(2) is unique to M. marinum and the M. tuberculosis complex and not present in any other sequenced mycobacterial species. M. marinum mutants with mutations in mel(1) and mel(2), constructed by allelic exchange, are defective in the ability to infect both murine and fish macrophage cell lines. These data suggest that the genes in mel(1) and mel(2) are important for the ability of M. marinum to infect host cells.