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TB bug inhibits any which way

There are multiple TB resistance pathways in the cell. KIRSCHNER/NAS

Each new study of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), seems to come up with a new resistance mechanism, and fails to see evidence for the mechanisms claimed by others. Now Stewart Chang, Jennifer Linderman, and Denise Kirschner (University of Michigan, Ann Arbor, MI) use a mathematical model to conclude that multiple mechanisms operate. Different mechanisms are best suited to protection under different conditions, and some are masked by experimental protocols used in previous studies.Mtb prevents macrophages from doing their job primarily by inhibiting antigen presentation by MHC class II. The Michigan group included four parts of this process (identified by others) that could be inhibited: MHC transcription; MHC protein maturation; antigen processing; and peptide loading onto MHC. IFN- and antigen got things going, and surface expression of peptide-loaded MHC was the readout.

Two inhibition classes served distinct time frames: effects were immediate for inhibition of antigen processing or peptide loading but delayed for inhibition of MHC transcription or maturation. The long pulses of IFN- used by two previous groups resulted in inhibition mediated primarily by effects on either maturation or transcription, respectively, with some part of the effect unexplained.

To suggest candidates for these unexplained effects, Kirschner and colleagues identified a number of processes whose inhibition in silico has major effects on antigen presentation efficiency. In vitro time series will allow many of the model's predictions to be tested.

Reference:

Chang, S.T., et al. 2005. Proc. Natl. Acad. Sci. USA. doi:10.1073/pnas0500362102

William A. Wells

wellsw{at}rockefeller.edu

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This Article Full Text (PDF, 265K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Social Bookmarking                            What's this?