TB bug inhibits any which way

JCB • VOLUME 168 • NUMBER 7 • 2005 986 TB bug inhibits any which way ach 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. IFNand 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 IFNused 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.