Tryptophan Biosynthesis Protects Mycobacteria from CD4 T-Cell-Mediated Killing

•Counteractomes are gene sets encoding determinants of Mtb survival to host immunity•CD4 T cells attempt to starve Mtb of tryptophan, an essential amino acid•Mtb can synthesize tryptophan under immune stress•Blocking Mtb tryptophan synthesis allows CD4 T cells to kill mycobacteria

SummaryBacteria 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 To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MP4 filesOptionsDownload video (9801 K)

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