Lipoprotein processing is required for virulence of Mycobacterium tuberculosis

• Published in: Molecular microbiology 2004-06, Vol.52 (6), p.1543-1552
• Main Authors: Sander, P., Rezwan, M., Walker, B., Rampini, S. K., Kroppenstedt, R. M., Ehlers, S., Keller, C., Keeble, J. R., Hagemeier, M., Colston, M. J., Springer, B., Böttger, E. C.
• Format: Article
• Language: English
• Subjects: Animals; Aspartic Acid Endopeptidases - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biological and medical sciences; Cell Line; Female; Fundamental and applied biological sciences. Psychology; Genes, Bacterial; Lipoproteins - metabolism; Lung - microbiology; Lung - pathology; Macrophages - microbiology; Mice; Mice, Inbred BALB C; Microbiology; Mutagenesis, Insertional; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - metabolism; Mycobacterium tuberculosis - pathogenicity; Protein Precursors - metabolism; Protein Processing, Post-Translational; Transferases - genetics; Transferases - metabolism; Tuberculosis - microbiology; Tuberculosis - pathology; Virulence - genetics
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/j.1365-2958.2004.04041.x

Summary Lipoproteins are a subgroup of secreted bacterial proteins characterized by a lipidated N‐terminus, processing of which is mediated by the consecutive activity of prolipoprotein diacylglyceryl transferase (Lgt) and lipoprotein signal peptidase (LspA). The study of LspA function has been limited mainly to non‐pathogenic microorganisms. To study a potential role for LspA in the pathogenesis of bacterial infections, we have disrupted lspA by allelic replacement in Mycobacterium tuberculosis, one of the world's most devastating pathogens. Despite the presence of an impermeable lipid outer layer, it was found that LspA was dispensable for growth under in vitro culture conditions. In contrast, the mutant was markedly attenuated in virulence models of tuberculosis. Our findings establish lipoprotein metabolism as a major virulence determinant of tuberculosis and define a role for lipoprotein processing in bacterial pathogenesis. In addition, these results hint at a promising new target for therapeutic intervention, as a highly specific inhibitor of bacterial lipoprotein signal peptidases is available.