Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Academic Article uri icon

abstract

  • Bacteria that cause disease rely on their ability to counteract and overcome host defenses. Here, we present a genome-scale study of Mycobacterium tuberculosis (Mtb) that uncovers the bacterial determinants of surviving host immunity, sets of genes we term "counteractomes." Through this analysis, we found that CD4 T cells attempt to contain Mtb growth by starving it of tryptophan--a mechanism that successfully limits infections by Chlamydia and Leishmania, natural tryptophan auxotrophs. Mtb, however, can synthesize tryptophan under stress conditions, and thus, starvation fails as an Mtb-killing mechanism. We then identify a small-molecule inhibitor of Mtb tryptophan synthesis, which converts Mtb into a tryptophan auxotroph and restores the efficacy of a failed host defense. Together, our findings demonstrate that the Mtb immune counteractomes serve as probes of host immunity, uncovering immune-mediated stresses that can be leveraged for therapeutic discovery.

published proceedings

  • Cell

altmetric score

  • 12.93

author list (cited authors)

  • Zhang, Y. J., Reddy, M. C., Ioerger, T. R., Rothchild, A. C., Dartois, V., Schuster, B. M., ... Rubin, E. J

citation count

  • 233

complete list of authors

  • Zhang, Yanjia J||Reddy, Manchi C||Ioerger, Thomas R||Rothchild, Alissa C||Dartois, Veronique||Schuster, Brian M||Trauner, Andrej||Wallis, Deeann||Galaviz, Stacy||Huttenhower, Curtis||Sacchettini, James C||Behar, Samuel M||Rubin, Eric J

publication date

  • December 2013

published in