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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 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]
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In the citing paper
“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]
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“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]
In the citing paper
“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]
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“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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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
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
“…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
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
“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
“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 68
“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
“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 80
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
“) 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
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
“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 66
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
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 71
“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 62
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
Targeting immunometabolism in host defence against Mycobacterium tuberculosis
Sheedy, F. J., & Divangahi, M. (2020) · Immunology · doi:10.1111/imm.13276 · Cited by 62
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
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 57
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 57
“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 58
“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 60
“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 52
“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
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 53
“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
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 53
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 52
“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
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
Healy, C. M., Gouzy, A., & Ehrt, S. (2020) · mBio · doi:10.1128/mbio.03315-19 · Cited by 49
“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
“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 50
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
“…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
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 46
“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
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
“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 44
“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 41
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 42
“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
Metadata
- 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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