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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]
In the citing paper
“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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InfluentialTryptophan as a Central Hub for Host/Microbial Symbiosis
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Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells
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Death of Mycobacterium tuberculosis by l -arginine starvation
Mizrahi, V., & Warner, D. F. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1813587115 · Cited by 21
Mechanism of Fluorinated Anthranilate-Induced Growth Inhibition in Mycobacterium tuberculosis
Islam, M. N., Hitchings, R., Kumar, S., Fontes, F. L., Lott, J. S., Kruh‐Garcia, N. A., & Crick, D. C. (2018) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.8b00092 · Cited by 21
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“This demonstrates that although Trp biosynthesis is not essential for in vitro growth, it is conditionally essential for the establishment and maintenance of infection (Smith et al., 2001; Zhang et al., 2013).”
BackgroundNasir, N., Anant, A., Vyas, R., & Biswal, B. K. (2016) · Scientific Reports · doi:10.1038/srep18880 · Cited by 20
Peng, F., Liu, Y., He, C., Kong, Y., Ouyang, Q., Xie, X.-N., Liu, T., Liu, Z., & Peng, J. (2018) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2018.02.051 · Cited by 20
Genetic Approaches to Facilitate Antibacterial Drug DevelopmentPreprint
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A tRNA modification in Mycobacterium tuberculosis facilitates optimal intracellular growth
Tomasi, F. G., 木村聡, Rubin, E. J., & Waldor, M. K. (2023) · eLife · doi:10.7554/elife.87146 · Cited by 19
“…Mtb tRNA modifications impact the pathogen’s growth in the host environment, we used the MtbTnDB transposon insertion sequencing (Tn-seq) database ( Zhang et al., 2013 ; Jinich et al., 2021 ) to determine if transposon insertions in genes encoding tRNA modifying enzymes have been associated with…”
Self-citationWang, X., Su, H.-W., Wallach, J. B., Wagner, J. C., Braunecker, B. J., Gardner, M. J., Guinn, K. M., Howard, N. C., Klevorn, T., Lin, K., et al. (2025) · Nature Microbiology · doi:10.1038/s41564-024-01913-5 · Cited by 25
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Jha, B., Kumar, D., Sharma, A., Dwivedy, A., Singh, R., & Biswal, B. K. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002299 · Cited by 18
“A recent study has demonstrated that tryptophan biosynthesis by Mtb is required to confer protection from T-cell mediated killing (2).”
BackgroundMethodSubramaniyam, S., DeJesus, M. A., Zaveri, A., Smith, C. M., Baker, R. E., Ehrt, S., Schnappinger, D., Sassetti, C. M., & Ioerger, T. R. (2019) · BMC Bioinformatics · doi:10.1186/s12859-019-3156-z · Cited by 18
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“Both rv0180c- and rv1592c-insertional mutants were also detected as highly attenuated at 10 and 45 days post-infection in another TnSeq study [17].”
BackgroundMethodConservation of the structure and function of bacterial tryptophan synthases
Michalska, K., Gale, J. P., Joachimiak, G., Chang, C., Hatzos-Skintges, C., Nocek, B. P., Johnston, S. E., Bigelow, L. J., Bajrami, B., Jedrzejczak, R. P., et al. (2019) · IUCrJ · doi:10.1107/s2052252519005955 · Cited by 18
“Recent studies exploring these avenues showed that anthranilate synthase component I, TrpE (Zhang et al., 2013), as well as functional tryptophan synthase are required for the survival of Mycobacterium tuberculosis in macrophage and mouse infection models, when an adaptive immune response trig- 650 Karolina Michalska…”
BackgroundMycobacterium tuberculosis SatS is a chaperone for the SecA2 protein export pathway
Miller, B. K., Hughes, R., Ligon, L. S., Rigel, N. W., Malik, S., Anjuwon-Foster, B. R., Sacchettini, J. C., & Braunstein, M. (2019) · eLife · doi:10.7554/elife.40063 · Cited by 17
“tuberculosis in macrophages Prior TraSH/Tnseq analyses using pooled libraries of transposon mutants predicted SatS to be required during murine and macrophage infections (Rengarajan et al., 2005; Zhang et al., 2013); however, this prediction had never been validated.”
Self-citationEvans, G. L., Gamage, S. A., Bulloch, E. M. M., Baker, E. N., Denny, W. A., & Lott, J. S. (2014) · ChemBioChem · doi:10.1002/cbic.201300628 · Cited by 17
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Self-citationMycobacterial tryptophan biosynthesis: A promising target for tuberculosis drug development?
Consalvi, S., Scarpecci, C., Biava, M., & Poce, G. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126731 · Cited by 18
“Moreover, it has been demonstrated that one of the host immune response after Mtb infection, is Trp starvation driven by CD4 T cells.(4) In the case of Trp, macrophages express indoleamine 2,3-dioxygenase (IDO) that catabolizes Trp to kynureine and other metabolites.”
BackgroundMethodXiao, G., Zhang, S., Zhang, L., Liu, S., Li, G., Ou, M., Zeng, X., Wang, Z., Zhang, G., & Lu, S. (2022) · BMC Microbiology · doi:10.1186/s12866-022-02659-y · Cited by 16
“tuberculosis can synthesize its own tryptophan de novo, which may be an adaptation for its survival during the degradation of tryptophan by IDO in host phagocytes [34].”
BackgroundDisentangling tryptophan metabolism in inflammatory bowel diseases
Becker, C., & Adolph, T. E. (2023) · Gut · doi:10.1136/gutjnl-2022-328853 · Cited by 18
Transposon sequencing reveals metabolic pathways essential for Mycobacterium tuberculosis infection
Block, A. M., Wiegert, P. C., Namugenyi, S. B., & Tischler, A. D. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1011663 · Cited by 16
“These include pathways for synthesis of the amino acids Met, Arg, Pro and Trp [13,18–21].”
BackgroundResultLearning from other diseases: protection and pathology in chronic fungal infections
Zelante, T., Pieraccini, G., Scaringi, L., Aversa, F., & Romani, L. R. (2015) · Seminars in Immunopathology · doi:10.1007/s00281-015-0523-3 · Cited by 17
Gharbi, R., Khanna, V., Frigui, W., Mhenni, B., Brosch, R., & Mardassi, H. (2021) · Scientific Reports · doi:10.1038/s41598-021-91737-8 · Cited by 16
Structure, mechanism and inhibition of anthranilate phosphoribosyltransferase
Scully, T. W., Jiao, W., Mittelstädt, G., & Parker, E. (2023) · Philosophical Transactions of the Royal Society of London. Biological Sciences · doi:10.1098/rstb.2022.0039 · Cited by 12
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Jinich, A., Zaveri, A., DeJesus, M. A., Spencer, A., Almada‐Monter, R., Flores‐Bautista, E., Smith, C. M., Sassetti, C. M., Rock, J. M., Ehrt, S., et al. (2025) · Molecular Microbiology · doi:10.1111/mmi.15370 · Cited by 15
Self-citationLibardo, M. D. J., Duncombe, C. J., Green, S. R., Wyatt, P. G., Thompson, S., Ray, P. C., Ioerger, T. R., Oh, S., Goodwin, M. B., Boshoff, H. I., et al. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.02.023 · Cited by 15
“On the other hand, the low FoRmutants that appeared with higher cell density had missense mutations in either anthranilate synthase subunit I (TrpE, rv1609), or the a or b subunit of tryptophan synthase (TrpA, rv1613; or TrpB, rv1612), all of which are essential enzymes in the tryptophan biosynthetic pathway (Wellingt…”
BackgroundInfluentialSelf-citationSrivastava, A., & Sinha, S. (2016) · Molecular BioSystems · doi:10.1039/c6mb00646a · Cited by 15
Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis
Lachmandas, E., Rios‐Miguel, A. B., Koeken, V. A. C. M., van der Pasch, E., Kumar, V., Matzaraki, V., Li, Y., Oosting, M., Joosten, L. A. B., Notebaart, R. A., et al. (2018) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiy173 · Cited by 15
“tuberculosis growth [4]; and a shift towards aerobic glycolysis in M.”
BackgroundInhibition of CorA-Dependent Magnesium Homeostasis Is Cidal in Mycobacterium tuberculosis
Park, Y., Ahn, Y., Jonnala, S. R., Oh, S., Fisher, J. M., Goodwin, M. B., Ioerger, T. R., Via, L. E., Bayliss, T., Green, S. R., et al. (2019) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01006-19 · Cited by 15
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From pathogenesis to antigens: the key to shaping the future of TB vaccines
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Discovery of antimicrobial agent targeting tryptophan synthase
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“This amino acid, together with L-arginine and L-glutamine, has been stated as a key regulator of immunometabolism in TB [35].”
Background
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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