Tryptophan Biosynthesis Protects Mycobacteria from CD4 T-Cell-Mediated Killing
Open accessAbstract
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.
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We can learn about these states from chronic stage mouse experiments and from in vitro experiments in starvation, late stationary phase and oxygen deprivation, during which growth stasis is observed.
“We can learn about these states from chronic stage mouse experiments48 and from in vitro experiments in starvation, late stationary phase and oxygen deprivation49, during which growth stasis is observed.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [48]
The methoxy mycolic acid synthase MmaA4 is more important in the chronic phase than the active phase of mouse infections, supporting the idea that oxygenated modifications predominate in stasis.
“The methoxy mycolic acid synthase MmaA4 is more important in the chronic phase than the active phase of mouse infections48,98, supporting the idea that oxygenated modifications predominate in stasis.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [48]
Our copy’s Results section compares gene requirements in infected mice, and its Discussion focuses on tryptophan biosynthesis and CD4-mediated stress. Searches for MmaA4, methoxy mycolic acid, and oxygenated modifications found no passage addressing whether MmaA4 matters more in chronic than active infection or whether those modifications predominate in stasis. (LLM, conf=0.76)
Experimental — accuracy not yet measuredM. tuberculosis is able to synthesize tryptophan.
“These observations could be recently traced back to the fact that M. tuberculosis is able to synthesize tryptophan, and thus IFN-γ-inducible activation of IDO and subsequent reduction in tryptophan availability fails to exert an anti-mycobacterial effect, whereas blockage of mycobacterial tryptophan synthesis increased the efficacy of this host defense mechanism (97).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [97]
IFN-γ-inducible activation of IDO and subsequent reduction in tryptophan availability fails to exert an anti-mycobacterial effect because M. tuberculosis can synthesize tryptophan.
“and thus IFN-γ-inducible activation of IDO and subsequent reduction in tryptophan availability fails to exert an anti-mycobacterial effect, whereas blockage of mycobacterial tryptophan synthesis increased the efficacy of this host defense mechanism (97).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [97]
Blockage of mycobacterial tryptophan synthesis increases the efficacy of IDO-mediated host defense.
“whereas blockage of mycobacterial tryptophan synthesis increased the efficacy of this host defense mechanism (97).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [97]
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Starvation Survival Response of Mycobacterium tuberculosis
Parish, T. (2003) · Journal of Bacteriology · doi:10.1128/jb.185.22.6702-6706.2003 · Cited by 77 · cited 3× · see citing works
“Interestingly, the trpE deletion strains die far more rapidly than a trpD deletion (Parish, 2003).”
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“IDO is thus required for IFN-g-mediated growth inhibition of Chlamydia and other Trp auxotrophic intracellular pathogens (Ibana et al., 2011; Zelante et al., 2009).”
Amino Acid Requirements of the Growing Mouse
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- Zelante T Fallarino F Bistoni F Puccetti P Romani L 2009b Indoleamine 2,3-dioxygenase in infection: the paradox of an evasive strategy that benefits the host Microbes and infection/Institut Pasteur 11 133 141 19007906
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Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease
Agus, A., Planchais, J., & Sokol, H. (2018) · Cell Host & Microbe · doi:10.1016/j.chom.2018.05.003 · Cited by 3,180 · see citing works
“Some bacteria, such as Mycobacterium tuberculosis, escape CD4-mediated defense by synthesizing their own Trp under stress conditions (Zhang et al., 2013).”
BackgroundTryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond
Platten, M., Nollen, E. A. A., Röhrig, U. F., Fallarino, F., & Opitz, C. A. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0016-5 · Cited by 1,586 · see citing works
Macrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989 · see citing works
“tuberculosis is able to synthesize tryptophan, and thus IFN-c-inducible activation of IDO and subsequent reduction in tryptophan availability fails to exert an anti-mycobacterial effect, whereas blockage of mycobacterial tryptophan synthesis increased the efficacy of this host defense mechanism (97).”
BackgroundHost Evasion and Exploitation Schemes of Mycobacterium tuberculosis
Cambier, C. J., Falkow, S., & Ramakrishnan, L. (2014) · Cell · doi:10.1016/j.cell.2014.11.024 · Cited by 432 · see citing works
Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis
Su, X., Gao, Y., & Yang, R. (2022) · Cells · doi:10.3390/cells11152296 · Cited by 424 · see citing works
The mycobacterial cell envelope — a moving target
Dulberger, C. L., Rubin, E. J., & Boutte, C. C. (2020) · Nature Reviews Microbiology · doi:10.1038/s41579-019-0273-7 · Cited by 365 · see citing works
Self-citationParthasarathy, A., Cross, P. J., Dobson, R. C. J., Adams, L. E., Savka, M. A., & Hudson, A. O. (2018) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2018.00029 · Cited by 361 · see citing works
“Anthranilates fluorinated at the 5- or 6- position of the benzene ring were demonstrated to be antibacterial, with modest in vivo activity in mouse models (Zhang et al., 2013).”
BackgroundMetabolic principles of persistence and pathogenicity in Mycobacterium tuberculosis
Ehrt, S., Schnappinger, D., & Rhee, K. (2018) · Nature Reviews Microbiology · doi:10.1038/s41579-018-0013-4 · Cited by 238 · see citing works
How sisters grow apart: mycobacterial growth and division
Kieser, K., & Rubin, E. (2014) · Nature Reviews Microbiology · doi:10.1038/nrmicro3299 · Cited by 260 · see citing works
Self-citationTryptophan and indole metabolism in immune regulation
Fiore, A., & Murray, P. J. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.12.001 · Cited by 262 · see citing works
Indoleamine 2,3‐dioxygenase 1 (IDO1): an up‐to‐date overview of an eclectic immunoregulatory enzyme
Pallotta, M. T., Rossini, S., Suvieri, C., Coletti, A., Orabona, C., Macchiarulo, A., Volpi, C., & Grohmann, U. (2021) · FEBS Journal · doi:10.1111/febs.16086 · Cited by 243 · see citing works
Role of indoleamine 2,3-dioxygenase in health and disease
Yeung, A. W. S., Terentis, A. C., King, N. J. C., & Thomas, S. R. (2015) · Clinical Science · doi:10.1042/cs20140392 · Cited by 235 · see citing works
HIF-1α Is an Essential Mediator of IFN-γ–Dependent Immunity to Mycobacterium tuberculosis
Braverman, J., Sogi, K. M., Benjamin, D. I., Nomura, D. K., & Stanley, S. A. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600266 · Cited by 233 · see citing works
Metabolic crosstalk between host and pathogen: sensing, adapting and competing
Olive, A. J., & Sassetti, C. M. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.12 · Cited by 228 · see citing works
The design and analysis of transposon insertion sequencing experiments
Chao, M. C., Abel, S., Davis, B. M., & Waldor, M. K. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2015.7 · Cited by 217 · see citing works
“…Con-ARTIST is not appropriate for the analysis of all TIS datasets, as it requires high library saturation (insertions at >50% of all potential insertion sites), and the use of related — rather than independently generated — transposon libraries for the determination of conditional essentiality.”
BackgroundGautam, U. S., Foreman, T. W., Bucşan, A. N., Veatch, A. V., Alvarez, X. A., Adékambi, T., Golden, N., Gentry, K. M., Doyle‐Meyers, L. A., Russell‐Lodrigue, K., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1711373114 · Cited by 193 · see citing works
“tuberculosis can synthesize its own Trp de novo (8), potentially an adaption for its survival during Trp catabolism by IDO in host phagocytes.”
BackgroundTargeting Bacterial Central Metabolism for Drug Development
Murima, P., McKinney, J. D., & Pethe, K. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.08.020 · Cited by 190 · see citing works
“In an elegant counter immunity screen, Zhang et al. (2013) recently demonstrated that the mycobacterial tryptophan biosynthetic pathway could be targeted by small-molecule inhibitors to promote the clearance ofM. tuberculosis in synergy with the immune system in infected animals (Zhang et al.,…”
BackgroundMolecular Determinants in Phagocyte-Bacteria Interactions
Kaufmann, S. H. E., & Dorhoi, A. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.014 · Cited by 189 · see citing works
“As a consequence, auxotrophic M. tuberculosis mutants for Trp are attenuated (Zhang et al., 2013).”
BackgroundThe microbiota, immunoregulation, and mental health: implications for public health
Lowry, C. A., Smith, D. G., Siebler, P. H., Schmidt, D., Stamper, C. E., Hassell, J. E., Yamashita, P. S., Fox, J. H., Reber, S. O., Brenner, L. A., et al. (2016) · Current Environmental Health Reports · doi:10.1007/s40572-016-0100-5 · Cited by 172 · see citing works
ARTIST: High-Resolution Genome-Wide Assessment of Fitness Using Transposon-Insertion Sequencing
Pritchard, J. R., Chao, M. C., Abel, S., Davis, B. M., Baranowski, C., Zhang, Y. J., Rubin, E. J., & Waldor, M. K. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004782 · Cited by 146 · see citing works
“We validate the ARTIST pipeline by reanalyzing a TIS dataset from a recent study of Mycobacterium tuberculosis requirements for growth in a mouse model of infection [7].”
BackgroundMethodInfluentialSelf-citationInducible antibacterial responses in macrophages
Sweet, M. J., Ramnath, D., Singhal, A., & Kapétanovic, R. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01080-y · Cited by 163 · see citing works
“Interestingly, Mtb counters tryptophan depletion mediated by CD4 + T cells and IFNγ by synthesizing its own tryptophan when host-derived tryptophan is Review article limiting 126 .”
Molecular basis of mycobacterial survival in macrophages
Awuh, J. A., & Flo, T. H. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2422-8 · Cited by 155 · see citing works
“However, IDO activation leads to breakdown of tryptophan that appears to be ineffective in controlling Mtb infection in mice as Mtb is able to synthesize tryptophan [264].”
BackgroundBraverman, J., & Stanley, S. A. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1700515 · Cited by 140 · see citing works
Bacterial Metabolism Shapes the Host–Pathogen Interface
Passalacqua, K. D., Charbonneau, M., & O’Riordan, M. X. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.vmbf-0027-2015 · Cited by 143 · see citing works
“tuberculosis, and that hypersusceptibility was reversed by inhibiting IDO or by addition of exogenous tryptophan (118).”
BackgroundBerney, M., Berney‐Meyer, L., Wong, K., Chen, B., Chen, M., Kim, J., Wang, J., Harris, D. E., Parkhill, J., Chan, J., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1513033112 · Cited by 139 · see citing works
“construct a mutant deficient in producing methionine, we surveyed bioinformatics databases and literature from genetic screens (8, 15).”
BackgroundBeites, T., O’Brien, K. M., Tiwari, D., Engelhart, C. A., Walters, S. B., Andrews, J., Yang, H., Sutphen, M. L., Weiner, D. M., Dayao, E. K., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12956-2 · Cited by 139 · see citing works
Self-citationGranulomas and Inflammation: Host-Directed Therapies for Tuberculosis
Ndlovu, H., & Marakalala, M. J. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00434 · Cited by 137 · see citing works
“identified a set of genes (the “counteractome”) required by Mtb to survive the immunological stress mediated by CD4+ T cells in mice (96).”
BackgroundInfluentialNitrogen metabolism in Mycobacterium tuberculosis physiology and virulence
Gouzy, A., Poquet, Y., & Neyrolles, O. (2014) · Nature Reviews Microbiology · doi:10.1038/nrmicro3349 · Cited by 133 · see citing works
Genomewide Assessment of Mycobacterium tuberculosis Conditionally Essential Metabolic Pathways
Minato, Y., Gohl, D. M., Thiede, J. M., Chacón, J. M., Harcombe, W. R., Maruyama, F., & Baughn, A. D. (2019) · mSystems · doi:10.1128/msystems.00070-19 · Cited by 132 · see citing works
“tuberculosis, several systematic genome-wide studies, including studies 81 using Tn-seq, have been performed to identify essential genes in vitro (7-16) and in vivo 82 (4).”
BackgroundCook, G. M., Hards, K., Dunn, E. A., Heikal, A., Nakatani, Y., Greening, C., Crick, D. C., Fontes, F. L., Pethe, K., Hasenoehrl, E., et al. (2017) · Microbiology Spectrum · doi:10.1128/microbiolspec.tbtb2-0014-2016 · Cited by 130 · see citing works
TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities
Carey, A. F., Rock, J. M., Krieger, I. V., Chase, M. R., Fernández-Suárez, M., Gagneux, S., Sacchettini, J. C., Ioerger, T. R., & Fortune, S. M. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1006939 · Cited by 123 · see citing works
Self-citationBarczak, A. K., Avraham, R., Singh, S., Luo, S. S., Zhang, W. R., Bray, M.-A., Hinman, A. E., Thompson, M., Nietupski, R. M., Golas, A., et al. (2017) · PLOS Pathogens · doi:10.1371/journal.ppat.1006363 · Cited by 120 · see citing works
“Rv0712 has been predicted to be essential in mice based on Tn-Seq experiments [43].”
BackgroundA small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase
Wellington, S., Nag, P. P., Michalska, K., Johnston, S. E., Jedrzejczak, R. P., Kaushik, V. K., Clatworthy, A. E., Siddiqi, N., McCarren, P. R., Bajrami, B., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2420 · Cited by 118 · see citing works
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“tuberculosis strain in human monocyte-derived macrophages (20).”
IL-32 is a molecular marker of a host defense network in human tuberculosis
Montoya, D. J., Inkeles, M. S., Liu, P. T., Realegeno, S. E., Teles, R. M. B., Vaidya, P., Munoz, M. A., Schenk, M., Swindell, W. R., Chun, R. F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009546 · Cited by 115 · see citing works
Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
Smith, C. M., Baker, R. E., Proulx, M. K., Mishra, B. B., Long, J. E., Park, S. W., Lee, H.-N., Kiritsy, M. C., Bellerose, M. M., Olive, A. J., et al. (2022) · eLife · doi:10.7554/elife.74419 · Cited by 125 · see citing works
Self-citationPenn, B. H., Netter, Z., Johnson, J. R., Dollen, J. V., Jang, G. Μ., Johnson, T. L., Ohol, Y. M., Maher, C., Bell, S. L., Geiger, K. M., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.010 · Cited by 114 · see citing works
Kieser, K. J., Boutte, C. C., Kester, J. C., Baer, C. E., Barczak, A. K., Méniche, X., Chao, M. C., Rego, E. H., Sassetti, C. M., Fortune, S. M., et al. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005010 · Cited by 114 · see citing works
“However, transposon mutagenesis data from M . tuberculosis H37Rv ( Mtb ) suggested that ponA1 (Rv0050, Entrez Gene ID 887065) could be disrupted without compromising proliferation of Mtb in culture[8], but that such a disruption would impact survival in a mouse model of TB[9].”
BackgroundSelf-citationImmunometabolism within the tuberculosis granuloma: amino acids, hypoxia, and cellular respiration
Qualls, J. E., & Murray, P. J. (2015) · Seminars in Immunopathology · doi:10.1007/s00281-015-0534-0 · Cited by 145 · see citing works
Cerebral tryptophan metabolism and outcome of tuberculous meningitis: an observational cohort study
van Laarhoven, A., Dian, S., Aguirre‐Gamboa, R., Ávila-Pacheco, J., Ricaño-Ponce, I., Ruesen, C., Annisa, J., Koeken, V. A. C. M., Chaidir, L., Li, Y., et al. (2018) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(18)30053-7 · Cited by 107 · see citing works
Succinate Dehydrogenase is the Regulator of Respiration in Mycobacterium tuberculosis
Hartman, T. E., Weinrick, B. C., Vilchèze, C., Berney, M., Tufariello, J. M., Cook, G. M., & Jacobs, W. R. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004510 · Cited by 106 · see citing works
“In terms of bioenergetic capacity, these studies revealed that one member of an operon containing a putative succinate dehydrogenase appeared to be essential for in vivo mycobacterial survival in a mouse model during the chronic phase of infection, a finding that was subsequently repeated using an analogous transposon…”
BackgroundMycobacterium tuberculosis MetabolismPreprint
Warner, D. F. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a021121 · Cited by 102 · see citing works
“…of kynurenine as a defining metabolite of active TB (Weiner et al. 2012b), because this is the product of the indoleamine2,3-dioxygenase-catalyzed degradation of tryptophan that, as detailed above, recent work has implicated in the host antimycobacterial response (Zhang et al. 2013b).”
BackgroundMethodInfluentialXu, W., DeJesus, M. A., Rücker, N., Engelhart, C. A., Wright, M. G., Healy, C., Lin, K., Wang, R., Park, S. W., Ioerger, T. R., et al. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01334-17 · Cited by 115 · see citing works
“We thus compared the results of our antibiotic susceptibility screens with those of a previous in vivo essentiality screen (17) to identify novel targets that could also potentiate the activity of other antibiotics.”
ResultSelf-citationTryptophan catabolism reflects disease activity in human tuberculosis
Collins, J. M., Siddiqa, A., Jones, D. P., Liu, K., Kempker, R. R., Nizam, A., Shah, N. S., Ismail, N. A., Ouma, S. G., Tukvadze, N., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.137131 · Cited by 100 · see citing works
“tuberculosis is able to synthesize tryptophan itself, allowing it to counter ongoing IDO activity without inhibiting mycobacterial growth (16).”
BackgroundNegatu, D. A., Gengenbacher, M., Dartois, V. A., & Dick, T. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.575586 · Cited by 104 · see citing works
Self-citationThe Tuberculous Granuloma and Preexisting Immunity
Cohen, S. B., Gern, B. H., & Urdahl, K. B. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-093019-125148 · Cited by 102 · see citing works
Rieck, B., Degiacomi, G., Zimmermann, M., Cascioferro, A., Boldrin, F., Adler, N. R. L., Bottrill, A. R., Chevalier, F. L., Frigui, W., Bellinzoni, M., et al. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006399 · Cited by 98 · see citing works
Solans, L., Aguiló, N., Samper, S., Pawlik, A., Frigui, W., Martı́n, C., Brosch, R., & Gonzalo‐Asensio, J. (2014) · Infection and Immunity · doi:10.1128/iai.01824-14 · Cited by 98 · see citing works
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“Figure 4B depicts as a positive control the expected suppressive effect of anthranilate and Trp on the inhibitory effect of fluoroanthranilate (12).”
InfluentialSelf-citationEvolution and emergence ofMycobacterium tuberculosis
Orgeur, M., Sous, C., Madacki, J., & Brosch, R. (2024) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuae006 · Cited by 92 · see citing works
“…essential genes of M. tuberculosis during in vitro growth conditions (Sassetti et al. 2003 , Griffin et al. 2011 , Rock et al. 2017 ) or genes that were essential for the survival of M. tuberculosis during infection conditions (Camacho et al. 1999 , Sassetti and Rubin 2003 , Zhang et al. 2013 ).”
BackgroundMicrobiota control of a tryptophan–AhR pathway in disease tolerance to fungi
Romani, L. R., Zelante, T., LUCA, A. D., Iannitti, R. G., Moretti, S., Bartoli, A., Aversa, F., & Puccetti, P. (2014) · European Journal of Immunology · doi:10.1002/eji.201344406 · Cited by 88 · see citing works
Targeting regulation of tryptophan metabolism for colorectal cancer therapy: a systematic review
Zhang, H., Zhang, A., Miao, J.-H., Sun, H. J., Yan, G., Wu, F., & Wang, X. (2019) · RSC Advances · doi:10.1039/c8ra08520j · Cited by 84 · see citing works
Mycobacterium tuberculosis: Pathogenesis and therapeutic targets
Yang, J.-X., Zhang, L., Qiao, W., & Luo, Y. (2023) · MedComm · doi:10.1002/mco2.353 · Cited by 80 · see citing works
The present state of the tuberculosis drug development pipeline
Libardo, M. D. J., Boshoff, H. I., & Barry, C. E. (2018) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2018.08.001 · Cited by 82 · see citing works
How macrophage heterogeneity affects tuberculosis disease and therapy
Russell, D. G., Simwela, N. V., Mattila, J. T., Flynn, J. L., Mwandumba, H., & Pisu, D. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-024-01124-3 · Cited by 68 · see citing works
A Mycobacterium tuberculosis Cytochrome bd Oxidase Mutant Is Hypersensitive to Bedaquiline
Berney, M., Hartman, T. E., & Jacobs, W. R. (2014) · mBio · doi:10.1128/mbio.01275-14 · Cited by 81 · see citing works
“tuberculosis with transposon insertions in cytochrome bd oxidase genes were underrepresented in mouse lungs after 48 days of infection (11).”
BackgroundMurugesan, D., Ray, P. C., Bayliss, T., Prosser, G. A., Harrison, J. R., Green, K., de Melo, C. S., Feng, T., Street, L. J., Chibale, K., et al. (2018) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.7b00275 · Cited by 80 · see citing works
Self-citationGiessen, T. W. (2022) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-040320-102858 · Cited by 80 · see citing works
The Expanding Diversity of Mycobacterium tuberculosis Drug Targets
Wellington, S., & Hung, D. T. (2018) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.7b00255 · Cited by 81 · see citing works
Sorrentino, F., del Río, R. G., Zheng, X., Matilla, J.-L. P., Torres, P. A., Martínez-Hoyos, M., Pérez‐Herrán, E., Mendoza-Losana, A., & Av‐Gay, Y. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01920-15 · Cited by 78 · see citing works
Mycobacterium tuberculosis biology, pathogenicity and interaction with the host
Warner, D. F., Barczak, A. K., Gutierrez, M. G., & Mizrahi, V. (2025) · Nature Reviews Microbiology · doi:10.1038/s41579-025-01201-x · Cited by 81 · see citing works
“…of M. tuberculosis to subvert host immunity was demonstrated in a screen that identified genes involved in tryptophan biosynthesis as key for bacillary survival against host CD4 T cell immunity, through the counteraction of tryptophan-depleting indoleamine 2,3-dioxygenase (IDO) pathway 112 .”
Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection
Hasenoehrl, E., Sajorda, D. R., Berney‐Meyer, L., Johnson, S., Tufariello, J. M., Fuhrer, T., Cook, G. M., Jacobs, W. R., & Berney, M. (2019) · Nature Communications · doi:10.1038/s41467-019-12224-3 · Cited by 74 · see citing works
Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans
Tafesse, F., Rashidfarrokhi, A., Schmidt, F. I., Freinkman, E., Dougan, S. K., Dougan, M. L., Esteban, A., Maruyama, T., Strijbis, K., & Ploegh, H. L. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005188 · Cited by 71 · see citing works
“Cells were lysed and MHC class I heavy chain [47] molecules were immunoprecipitated, treated with Endo H, and analyzed by SDS/PAGE and autoradiography.”
MethodPalace, S. G., Proulx, M. K., Lu, S., Baker, R. E., & Goguen, J. D. (2014) · mBio · doi:10.1128/mbio.01385-14 · Cited by 68 · see citing works
“Tn-seq is an increasingly popular tool in studies of bacterial pathogens (14, 16–31), although to date only five pathogens have been examined using animal infection as a selection regime (Streptococcus pneumoniae [23, 26], Haemophilus influenzae [16], Yersinia pseudotuberculosis [25], uropathogenic Escherichia coli [3…”
MethodMemari, B., Bouttier, M., Dimitrov, V., Ouellette, M., Behr, M. A., Fritz, J. H., & White, J. H. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1501141 · Cited by 67 · see citing works
“tuberculosis is capable of inducing Trp biosynthesis under stress conditions (52, 53), suggesting that induced Trp metabolism contributes to host responses to infection by other mechanisms.”
BackgroundNunes, J. E. S., Duque-Villegas, M. A., de Freitas, T. F., Galina, L., Timmers, L. F. S. M., Bizarro, C. V., Machado, P., Basso, L. A., & Ducati, R. G. (2020) · Molecules · doi:10.3390/molecules25061259 · Cited by 67 · see citing works
“tuberculosis, however, can synthesize tryptophan (from chorismate precursor) under stress conditions and, thus, starvation fails [23].”
BackgroundMicrobiome-immune interactions in tuberculosis
Mori, G., Morrison, M., & Blumenthal, A. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009377 · Cited by 77 · see citing works
Transposon sequencing: methods and expanding applications
Kwon, Y. M., Ricke, S. C., & Mandal, R. K. (2015) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-015-7037-8 · Cited by 63 · see citing works
“) as exemplified in several studies shown in Table 2 (Carter et al. 2014; Goodman et al. 2009; Wong et al. 2013; Wu et al. 2015; Zhang et al. 2013).”
Gut Microbiota in Liver Disease: What Do We Know and What Do We Not Know?
Jiang, L., & Schnabl, B. (2020) · Physiology · doi:10.1152/physiol.00005.2020 · Cited by 64 · see citing works
Liu, X., Yang, M., Xu, P., Du, M., Li, S., Shi, J. P., Li, Q., Yuan, J., & Pang, Y. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-024-01230-1 · Cited by 65 · see citing works
“Four hours after Mtb infection, the infected cells were washed three times with 1× PBS and incubated again with fresh DMEM.”
The tryptophan biosynthetic pathway is essential forMycobacterium tuberculosisto cause disease
Lott, J. S. (2020) · Biochemical Society Transactions · doi:10.1042/bst20200194 · Cited by 64 · see citing works
Osman, M. M., Shanahan, J. K., Chu, F., Takaki, K. K., Pinckert, M. L., Pagán, A. J., Brosch, R., Conrad, W. H., & Ramakrishnan, L. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2122161119 · Cited by 60 · see citing works
Propionate prevents loss of the PDIM virulence lipid in Mycobacterium tuberculosis
Mulholland, C. V., Wiggins, T. J., Cui, J., Vilchèze, C., Saranathan, R., Shultis, M. W., Reyes-Fernández, E. Z., Jacobs, W. R., & Berney, M. (2024) · Nature Microbiology · doi:10.1038/s41564-024-01697-8 · Cited by 62 · see citing works
“Moreover, today, in the emerging era of Mtb systems biology in which large pools of genetically modified strains are crucial tools for in vitro and in vivo studies 54–56 , preventing secondary PDIM mutations is imperative to prevent potential misattribution of phenotypes to genotypes.”
Sharma, A., Rosa, M. D., Singla, N., Singh, G., Barnwal, R. P., & Pandey, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01833 · Cited by 61 · see citing works
Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity
Brady, P. N., Goel, A., & Johnson, M. A. (2019) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00038-18 · Cited by 58 · see citing works
Targeting immunometabolism in host defence against Mycobacterium tuberculosis
Sheedy, F. J., & Divangahi, M. (2020) · Immunology · doi:10.1111/imm.13276 · Cited by 59 · see citing works
Unconventional screening approaches for antibiotic discovery
Farha, M. A., & Brown, E. D. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12803 · Cited by 56 · see citing works
Mycobacterium tuberculosis Metabolism
Mashabela, G. T., de Wet, T. J., & Warner, D. F. (2019) · Microbiology Spectrum · doi:10.1128/microbiolspec.gpp3-0067-2019 · Cited by 56 · see citing works
Park, J.-H., Shim, D., Kim, K. E. S., Lee, W., & Shin, S. J. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.635335 · Cited by 56 · see citing works
“The combined effect of 2-amino-6fluorobenzoic acid (6-FABA), a small molecule that inhibits TrpE, and IFN-g showed clear 40-fold synergy in mice and nine-fold synergy in human macrophages (Zhang et al., 2013).”
BackgroundWestrop, G. D., Williams, R., Wang, L., Zhang, T., Watson, D. G., Silva, A. M., & Coombs, G. H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0136891 · Cited by 56 · see citing works
“One good example is the case ofMycobacterium tuberculosis, and, interestingly, it was recently reported that the pathogen can overcome immunity and so become persistent by activating genes enabling it to synthesise tryptophan de novo [47].”
BackgroundMartin, C. J., Carey, A. F., & Fortune, S. M. (2015) · Seminars in Immunopathology · doi:10.1007/s00281-015-0533-1 · Cited by 57 · see citing works
“This robs Mtb of tryptophan, and tryptophan biosynthetic mutants are exquisitely sensitive to IFN-γ mediated killing [50].”
BackgroundGenome-wide epistasis and co-selection study using mutual information
Pensar, J., Puranen, S., Arnold, B., MacAlasdair, N., Kuronen, J., Tonkin‐Hill, G. Q., Pesonen, M., Xu, Y., Sipola, A., Sánchez-Busó, L., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz656 · Cited by 54 · see citing works
“Tryptophan synthesis is a crucial part of protein biosynthesis, and its synthesis has been linked to greater virulence in other bacterial species by allowing for immune evasion (47).”
BackgroundDwivedy, A., Ashraf, A., Jha, B., Kumar, D., Agarwal, N., & Biswal, B. K. (2021) · Communications Biology · doi:10.1038/s42003-021-01926-4 · Cited by 53 · see citing works
Mycobacterial genes essential for the pathogen's survival in the host
Ehrt, S., Rhee, K. Y., & Schnappinger, D. (2015) · Immunological Reviews · doi:10.1111/imr.12256 · Cited by 52 · see citing works
“A striking example highlighting a mycobacterial mechanism of resisting host immunity came from a search for Mtb genes that protect the pathogen from CD4 T-cellmediated host immunity (72).”
BackgroundDistinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis
Bellerose, M. M., Proulx, M. K., Smith, C. M., Baker, R. E., Ioerger, T., & Sassetti, C. (2020) · mSystems · doi:10.1128/msystems.00396-20 · Cited by 48 · see citing works
Self-citationLi, Y., Liu, N., Ge, Y., Yang, Y., Ren, F., & Wu, Z. (2022) · European Journal of Immunology · doi:10.1002/eji.202149401 · Cited by 51 · see citing works
Exploring NAD+ metabolism in host–pathogen interactions
Mesquita, I., Varela, P., Belinha, A., Gaifem, J., Laforge, M., Vergnes, B., Estaquier, J., & Silvestre, R. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2119-4 · Cited by 51 · see citing works
“tuberculosis growth by starving out of tryptophan [108].”
BackgroundThe Role of Amino Acids in Tuberculosis Infection: A Literature Review
Amalia, F. I., Syamsunarno, M. R. A. A., Triatin, R. D., Fatimah, S. N., Chaidir, L., & Achmad, T. H. (2022) · Metabolites · doi:10.3390/metabo12100933 · Cited by 48 · see citing works
Determining the Pathogenicity of Genetic Variants Associated with Cardiac Channelopathies
Campuzano, Ó., Allegue, C., Fernandez, A., Iglesias, A., & Brugada, R. (2015) · Scientific Reports · doi:10.1038/srep07953 · Cited by 50 · see citing works
Healy, C. M., Gouzy, A., & Ehrt, S. (2020) · mBio · doi:10.1128/mbio.03315-19 · Cited by 49 · see citing works
“tuberculosis in the spleen of mice (23); perhaps the”
BackgroundTCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis
Collins, J. M., Jones, D. P., Sharma, A., Khadka, M., Liu, K., Kempker, R. R., Prideaux, B., Maner-Smith, K. M., Tukvadze, N., Shah, N. S., et al. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009941 · Cited by 49 · see citing works
“Thus, accumulating TCA cycle intermediates and decreased itaconate during later stages of TB disease may be another example of Mtb exploiting a host metabolic adaption aimed at controlling Mtb replication during the initial stages of infection [32,33].”
BackgroundMycobacterium tuberculosis in the Face of Host-Imposed Nutrient Limitation
Berney, M., & Berney‐Meyer, L. (2017) · Microbiology Spectrum · doi:10.1128/microbiolspec.tbtb2-0030-2016 · Cited by 47 · see citing works
Perkowski, E. F., Miller, B. K., McCann, J. R., Sullivan, J. T., Malik, S., Allen, I. C., Godfrey, V., Hayden, J., & Braunstein, M. (2015) · Molecular Microbiology · doi:10.1111/mmi.13303 · Cited by 46 · see citing works
“…hereafter referred to as omamA, results in a growth defect in resting murine bone-marrow derived macrophages (McCann et al., 2011) and TraSH analysis of a pooled M. tuberculosis mutant library in mice predicts a role for OmamA during host infection (Sassetti and Rubin, 2003; Zhang et al., 2013).”
BackgroundThe cross-talk between opportunistic fungi and the mammalian host via microbiota’s metabolism
Romani, L., Zelante, T., Palmieri, M., Napolioni, V., Picciolini, M., Velardi, A., Aversa, F., & Puccetti, P. (2015) · Seminars in Immunopathology · doi:10.1007/s00281-014-0464-2 · Cited by 47 · see citing works
Translational Research in the Nonhuman Primate Model of Tuberculosis
Foreman, T. W., Mehra, S., Lackner, A. A., & Kaushal, D. (2017) · ILAR Journal · doi:10.1093/ilar/ilx015 · Cited by 45 · see citing works
“Mtb can, however, synthesize its own Trp (Zhang and Rubin 2013; Zhang et al. 2013), and thus the induction of IDO1 in Mtb-infected lesions is unable to contain bacillary replication; rather it dampens productive immune responses.”
BackgroundIlluminating Host-Mycobacterial Interactions with Genome-wide CRISPR Knockout and CRISPRi Screens
Lai, Y., Babunovic, G. H., Cui, L., Dedon, P. C., Doench, J. G., Fortune, S. M., & Lu, T. K. (2020) · Cell Systems · doi:10.1016/j.cels.2020.08.010 · Cited by 42 · see citing works
Lien, K. A., Nichols, R. J., Cassidy-Amstutz, C., Dinshaw, K., Knight, M., Singh, R., Eltis, L. D., Savage, D. F., & Stanley, S. A. (2021) · eLife · doi:10.7554/elife.74358 · Cited by 44 · see citing works
“A transposon screen has identified Cfp29 as a gene required for growth in mice (Zhang et al., 2013) and Cfp29 has long been known as an immunodominant T cell antigen in both mice and human TB patients (Weldingh and Andersen, 1999).”
Ankley, L. M., Thomas, S. M., & Olive, A. J. (2020) · Infection and Immunity · doi:10.1128/iai.00916-19 · Cited by 43 · see citing works
“tuberculosis is able to evade direct killing by T cells through metabolic functions such as de novo tryptophan synthesis that bypasses the induction of indoleamine 2,3 dioxygenase (IDO) and tryptophan restriction in host cells (30).”
BackgroundMycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence
Dong, W., Nie, X., Zhu, H. M., Liu, Q., Shi, K.-X., You, L., Zhang, Y., Fan, H. C., Yan, B., Niu, C., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2019305118 · Cited by 43 · see citing works
Self-citationCell-Autonomous Effector Mechanisms against Mycobacterium tuberculosisPreprint
MacMicking, J. D. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a018507 · Cited by 40 · see citing works
“Both offer hope for shortening treatment as well as for tackling the problem of bacterial multidrug resistance (Singh et al. 2008; Zhang et al. 2013; Stanley et al. 2014).”
Influential
- Authors
- Zhang, Y. J., Reddy, M. C., Ioerger, T. R., Rothchild, A. C., Dartois, V., Schuster, B. M., Trauner, A., Wallis, D., Galaviz, S., Huttenhower, C., Sacchettini, J. C., Behar, S. M., & Rubin, E. J.
- Affiliations
- Harvard University (US)
- Texas A&M University (US)
- University of Massachusetts Chan Medical School (US)
- Rutgers New Jersey Medical School (US)
- Corresponding author
- Rubin, Eric J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 155
- Issue
- 6
- Pages
- 1296-1308
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3902092
- OpenAlex
- W1983275536
- Cited by
- 351
- References
- 64
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 23 · 2023: 31 · 2022: 31 · 2021: 37 · 2020: 32 · 2019: 42 · 2018: 21 · 2017: 22 · 2016: 19 · 2015: 27 · 2014: 23 · 2013: 1
- FWCI
- 16.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Cambridge
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Allergy and Infectious Diseases (R01AI098637, R01AI106725, P01AI095208)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Mycobacterium tuberculosis, tryptophan biosynthesis, tryptophan auxotrophy, host-pathogen interaction, tryptophan starvation, small molecule inhibitors, host immunity, tuberculosis immunology
- MeSH terms
- Animals, Humans, Interferon-gamma, Macrophages, Mice, Inbred C57BL, Mycobacterium tuberculosis, Tryptophan, Tuberculosis, CD4-Positive T-Lymphocytes, Mycobacterium smegmatis, Virulence Factors, Indoleamine-Pyrrole 2,3,-Dioxygenase, Mice, Biosynthetic Pathways, ortho-Aminobenzoates
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