TY - JOUR
T1 - XTryptophan biosynthesis protects mycobacteria from CD4 T-Cell-mediated Killing
AU - Zhang, Yanjia J.
AU - Reddy, Manchi C.
AU - Ioerger, Thomas R.
AU - Rothchild, Alissa C.
AU - Dartois, Veronique
AU - Schuster, Brian M.
AU - Trauner, Andrej
AU - Wallis, Deeann
AU - Galaviz, Stacy
AU - Huttenhower, Curtis
AU - Sacchettini, James C.
AU - Behar, Samuel M.
AU - Rubin, Eric J.
N1 - Funding Information:
We thank Michael DeJesus, Chris Sassetti, and Justin Pritchard for their ongoing collaboration and thoughtful conversations about genomic profiling in Mtb. We thank Xiaohua Li and Spandana Valluru for technical support. Noman Sidddiqi and Larry Pipkin manage and run our BL3 facility; we thank them for their support. We thank our tremendous scientific community, including Marcia Goldberg, Laurence Rahme, Sarah Fortune, and Barry Bloom, for its constant support and feedback. The project described was supported by the National Institutes of Health (T32 GM007753 to Y.J.Z., R01 AI 098637 to S.M.B., and P01 AI095208 to J.C.S. and E.J.R.), the Herchel Smith Graduate Fellowship of Harvard and Cambridge University (to Y.J.Z.), and the Wolfe-Welch Chair (to J.C.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2013/12/5
Y1 - 2013/12/5
N2 - 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. PaperFlick
AB - 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. PaperFlick
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U2 - 10.1016/j.cell.2013.10.045
DO - 10.1016/j.cell.2013.10.045
M3 - Article
C2 - 24315099
AN - SCOPUS:84890037649
SN - 0092-8674
VL - 155
SP - X1296-1308
JO - Cell
JF - Cell
IS - 6
ER -