In response to the NIH Program Announcement calling for more basic information regarding the biology, immunology and pathogenesis of this disease, the investigators present the hypothesis that past failures in vaccine development against tuberculosis have been due to the inability to emulate the immunogenicity of the whole bacillus due to failure to recognize the importance of appendages that covalently modify key protective protein antigens. The differential immunological reactivity of native and E. coli recombinant forms of mycobacterial proteins as well as our own preliminary data support this principle. Recently, the investigators provided definitive chemical proof that some M tuberculosis proteins are glycosylated. They have now extended these studies to demonstrate that the M tuberculosis proteome possesses a number of such structures and that glycosylation plays a direct role in immunological recognition of M tuberculosis proteins, facts which now portend new approaches to vaccine and serodiagnostic antigen development. To address the issue of the contribution of aprotein components to immunological recognition of protein antigens, they will (i) exploit their proven strengths in protein chemistry to demonstrate the relative abundance of glycoproteins in the M tuberculosis proteome and provide a precise chemical characterization for a large number of these molecules; (ii) apply this structural information, some of which is already in hand, to immunological assays in both the human and murine systems, to provide a detailed understanding of how the host's acquired immune system responds to M tuberculosis glycoproteins; and (iii) initiate studies of the biosynthesis of the post-translationally modified, and specifically mannosylated, proteins, which will yield information and new tools for full evaluation of the general biological, particularly immunological, significance of protein glycosylation and lipidation.
| VanderVen, Brian C; Harder, Jeffery D; Crick, Dean C et al. (2005) Export-mediated assembly of mycobacterial glycoproteins parallels eukaryotic pathways. Science 309:941-3 |
| Turner, Joanne; Dobos, Karen M; Keen, Marc A et al. (2004) A limited antigen-specific cellular response is sufficient for the early control of Mycobacterium tuberculosis in the lung but is insufficient for long-term survival. Infect Immun 72:3759-68 |
