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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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“However,severalstudieshaveshownthat geneticrequirementsidenti fi edbyTnSeqaregenerallycon fi rmedinaerosol route infections 13,16,17,83 .”
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“Especially in recent years, MTB has adapted to escape starvation and survive within macrophages by independently synthesizing its amino acids [22, 23], which may improve conditions for tuberculosis with low bacterial loads or in hidden disease sites.”
Translating genomics research into control of tuberculosis: lessons learned and future prospects
Warner, D. F., & Mizrahi, V. (2014) · Genome biology · doi:10.1186/s13059-014-0514-z · Cited by 3
“[57] used Tn-Seq to identify sets of genes which the tubercle bacillus engages in order to survive host immunity - so-called ‘counteractomes’ - thereby uncovering a key role for de novo tryptophan biosynthesis in preventing the killing of M.”
MethodKhan, S. H., Bijpuria, S., Maurya, A., & Taneja, B. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.08.236 · Cited by 3
Jurkowitz, M. S., Azad, A. K., Monsma, P. C., Keiser, T. L., Kanyo, J. E., Lam, T. T., Bell, C. E., & Schlesinger, L. S. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101849 · Cited by 3
“tb in mice during a transposon mutagenesis screen (70) and was not found to be upregulated in resting or activated mouse bone marrow macrophages (71), subsequent studies have indicated that the essentiality of a gene or its regulation is dependent on the system being studied.”
BackgroundMycobacterial Genetic Technologies for Probing the Host-Pathogen Microenvironment
Adefisayo, O. O., Curtis, E. R., & Smith, C. M. (2023) · Infection and Immunity · doi:10.1128/iai.00430-22 · Cited by 3
“(106) utilized a fully saturated TnSeq library in major histocompatibility complex (MHC) knockout B6 mice to study the effect of CD41”
MethodExpanding structural diversity of 5′-aminouridine moiety of sansanmycin via mutational biosynthesis
Lu, Y., Li, Y., Fan, J., Li, X., Sun, H., Wang, L., Han, X., Zhu, Y., Zhang, T., Shi, Y., et al. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1278601 · Cited by 3
Tryptophan and Its Derived Metabolites as Biomarkers for Tuberculosis Disease: A Systematic Review
Maulina, N., Hayati, Z., Hasballah, K., & Zulkarnain, Z. (2024) · ̒Ulūm va funūn-i bastah/bandī · doi:10.61186/ibj.4174 · Cited by 3
“Despite this, MTb has the ability to synthesize Trp, thereby counteracting the action of IDO without affecting its growth [18] .”
BackgroundConsalvi, S., Venditti, G., Zhu, J., Boshoff, H. I., Arora, K., Logu, A. D., Ioerger, T. R., Rubin, E. J., Biava, M., & Poce, G. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113843 · Cited by 3
Self-citationSubramaniyam, S., Zaveri, A., DeJesus, M. A., Smith, C. M., Baker, R. E., Ehrt, S., Schnappinger, D., Sassetti, C. M., & Ioerger, T. R. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/590281 · Cited by 3
Self-citationKhan, M. Z., Hunt, D. M., Singha, B., Kapoor, Y., Singh, N. K., Prasad, D. V. S., Sriram, D., Sowpati, D. T., de Carvalho, L. P. S., & Nandicoori, V. K. (2023) · eLife · doi:10.7554/elife.91970 · Cited by 2
Shi, C., Liu, X., Chen, D., Wang, T., Wang, Y., Cai, N., Li, Z., Hu, Y., Cai, Y., & Chen, X. (2025) · iScience · doi:10.1016/j.isci.2025.114102 · Cited by 2
Essential redundancies fuel Mycobacterium tuberculosis adaptation to the host
Silva, M., Pinto, A. J., & Beites, T. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1013749 · Cited by 2
“In bacterial pathogens, genetic screens during infection identified conditionally essential genes in vivo that are dispensable for in vitro bacterial growth [10].”
InfluentialSharma, A., Singh, G., & Shrivastava, R. (2026) · Drug Development Research · doi:10.1002/ddr.70239 · Cited by 3
“Tryptophan synthesis is prominently inhibited by fluorinated anthranilates; however their precise target remains unclear (Zhang et al. 2013).”
Padilla‐Gómez, J., McGinn, R. A., Andrade, V., Liang, Y., Libby, K. A., Ni, H. M., Ringel, A. E., Evavold, C. L., & Bryson, B. D. (2026) · mSphere · doi:10.1128/msphere.00141-26 · Cited by 2
“We therefore tested if these factors accounted for the observed ILI formation in murine versus human macrophages (8, 11, 21, 22).”
Mycobacterium tuberculosis Metabolism
Mashabela, G. T., de Wet, T. J., & Warner, D. F. (2019) · ASM Press eBooks · doi:10.1128/9781683670131.ch67 · Cited by 2
Mycobacterial quorum quenching and biofilm inhibition potential of medicinal plants
Seaman, J. L., Oosthuizen, C. B., Gibango, L., & Lall, N. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90999-0.00008-2 · Cited by 2
Konas, D. W., Cho, S., Thomas, O., Bhatti, M. M., Hernandez, K. L., Moran, C., Booter, H., Candela, T., Lacap, J., McFadden, P., et al. (2023) · ACS Bio & Med Chem Au · doi:10.1021/acsbiomedchemau.3c00029 · Cited by 2
Samuels, V., Mulelu, A. E., Ndlovu, H., & Marakalala, M. J. (2024) · Microbiology Spectrum · doi:10.1128/spectrum.02515-23 · Cited by 2
“In Mtb , FtsEX has been implicated as an important contributor to the pathogen’s evasion of CD4-mediated immune responses in a genome-wide transposon site hybridization approach (9).”
BackgroundMohan, S., Jade, D., Gupta, S., Ayyamperumal, S., Chandrasekar, M., & Nanjan, M. J. (2022) · Molecular Simulation · doi:10.1080/08927022.2021.2015069 · Cited by 2
“The potential of TRPS as an under-exploited and novel target for antitubercular target has been well recognised [7, 16, 17].”
BackgroundDraft Genome Sequence of Mycobacterium chimaera Type Strain Fl-0169
Pfaller, S. L., Tokarev, V., Kessler, C., McLimans, C. J., Gomez‐Alvarez, V., Wright, J., King, D. N., & Lamendella, R. (2017) · Genome Announcements · doi:10.1128/genomea.01620-16 · Cited by 2
Amino acid metabolism in fate decision of porcine immune cells: advances and beyond
Ren, W., Peng, B. I. N., Xia, Y., & Zhu, G. (2020) · Scientia Sinica Vitae · doi:10.1360/ssv-2020-0041 · Cited by 2
Jackson, M. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.07.019 · Cited by 2
Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells
Gaudet, R. G., Bradfield, C. J., & MacMicking, J. D. (2017) · ASM Press eBooks · doi:10.1128/9781555819194.ch34 · Cited by 2
The Sec Pathways and Exportomes of Mycobacterium tuberculosis
Miller, B. K., Zulauf, K. E., & Braunstein, M. (2017) · ASM Press eBooks · doi:10.1128/9781555819569.ch28 · Cited by 2
Indole‐3‐Glycerol Phosphate Synthase From Mycobacterium tuberculosis: A Potential New Drug Target
Esposito, N., Konas, D. W., & Goodey, N. M. (2021) · ChemBioChem · doi:10.1002/cbic.202100314 · Cited by 2
mSphere of Influence: Combining Host and Pathogen Genetics To Disrupt Chronic Infections
Olive, A. J. (2020) · mSphere · doi:10.1128/msphere.00106-20 · Cited by 2
Drosophila melanogaster is a powerful host model to study mycobacterial virulencePreprint
Fuentes, E., Sivakumar, N., Selvik, L.-K. M., Arch, M., Cardona, P.-J., Ioerger, T. R., & Dragset, M. S. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.12.491628 · Cited by 2
“genome-wide manner using mouse (16, 17, 20, 21), cattle (22), or ameba (23, 24) as host infection models.”
BackgroundMethodResultSelf-citationOlive, A. J. (2025) · mSphere · doi:10.1128/msphere.00517-24 · Cited by 1
Deciphering macrophage dynamics and immune evasion strategies by the intracellular bacteria
Munir, F., He, B., Shakoor, A., Liu, J., & Ma, W. (2025) · Immunologic Research · doi:10.1007/s12026-025-09696-5 · Cited by 1
“Interestingly, Mtb countered the depletion of tryptophan by IFN-γ and CD4 + T cells by synthesizing its own tryptophan [71].”
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Inhibitors of nutrient pathways: nature's overlooked antibiotic arsenal
Gordzevich, R., Jin, K.-Y., Ashe, J. M., & Brown, E. D. (2026) · Natural Product Reports · doi:10.1039/d6np00036c · Cited by 1
Metabolic Host Response to Intracellular Infections
Ferreira, C. M., Barbosa, A. M., Pereira, I. M., & Torrado, E. (2018) · Experientia supplementum · doi:10.1007/978-3-319-74932-7_8 · Cited by 1
Neves, C. E., Paz, J. D., Abbadi, B. L., Rambo, R. S., Czeczot, A. D. M., Sperotto, N. D. D. M., Dadda, A. D. S., Silva, R. B. M., Perelló, M. A., Gonçalves, G. A., et al. (2024) · ACS Omega · doi:10.1021/acsomega.4c03981 · Cited by 1
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“Recent studies show that the tryptophan (Trp) biosynthetic pathway plays an important role in the Mycobacterium tuberculosis growth and replication [2].”
BackgroundmSphere of Influence: the Complexity of Interferon Gamma-Mediated Pathogen Control
Bryson, B. D. (2021) · mSphere · doi:10.1128/msphere.01295-20 · Cited by 1
Penn, 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. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/202598 · Cited by 1
“While elegant genetic studies have implicated dozens of secreted Mtb factors in virulence (Sassetti and Rubin, 2003; Y. J. Zhang et al., 2013), whether these factors directly interact with host molecules to influence macrophage physiology is unknown.”
Fishbein, S. R. S., Wolf, I. D., Dulberger, C. L., Wang, A., Keshishian, H., Wallace, L., Carr, S. A., Ioerger, T. R., Rego, E. H., & Rubin, E. J. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/872341 · Cited by 1
“In fact, these data suggest, that while lepA is non-essential for in vitro growth of 248 Mycobacterium tuberculosis (Mtb), lepA- strains grow poorly during murine infection [65].”
BackgroundSelf-citation
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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