title: Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing.
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.
authors: Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Yanjia J
authors: YJ
authors: Zhang
authors: Manchi C
authors: MC
authors: Reddy
authors: Thomas R
authors: TR
authors: Ioerger
authors: Alissa C
authors: AC
authors: Rothchild
authors: Veronique
authors: V
authors: Dartois
authors: Brian M
authors: BM
authors: Schuster
authors: Andrej
authors: A
authors: Trauner
authors: Deeann
authors: D
authors: Wallis
authors: Stacy
authors: S
authors: Galaviz
authors: Curtis
authors: C
authors: Huttenhower
authors: James C
authors: JC
authors: Sacchettini
authors: Samuel M
authors: SM
authors: Behar
authors: Eric J
authors: EJ
authors: Rubin
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D014364:Tryptophan / Q000096:biosynthesis*; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology*; D037521:Virulence Factors / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: C586441:2-amino-5-fluorobenzoic acid; C586442:2-amino-6-fluorobenzoic acid; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D037521:Virulence Factors; D062367:ortho-Aminobenzoates; D007371:Interferon-gamma; D014364:Tryptophan