The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.
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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Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · cited 1×
“We created conditionally required gene sets as well as ranked gene lists for each condition, which allowed us to compare gene sets using the running-sum enrichment analysis in the GSEA tool (Subramanian et al., 2005).”
An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection.
Flynn, J. L., Chan, J., Triebold, K. J., Dalton, D. K., Stewart, T. A., & Bloom, B. R. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.178.6.2249 · Cited by 2,468 · cited 1×
“…shown that the Th1 subset is especially effective in limiting Mtb growth, and cytokines such as IFN-g and TNF-a are needed in some, but not all, models of CD4 T cell-mediated defenses (Bold et al., 2011; Flynn et al., 1993, 1995; Gallegos et al., 2011; Nandi and Behar, 2011; Scanga et al., 2000).”
Protein and amino acid requirements in human nutrition.
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Disseminated tuberculosis in interferon gamma gene-disrupted mice.
Cooper, A. M., Dalton, D. K., Stewart, T. A., Griffin, J. P., Russell, D. G., & Orme, I. M. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.178.6.2243 · Cited by 1,987
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“…shown that the Th1 subset is especially effective in limiting Mtb growth, and cytokines such as IFN-g and TNF-a are needed in some, but not all, models of CD4 T cell-mediated defenses (Bold et al., 2011; Flynn et al., 1993, 1995; Gallegos et al., 2011; Nandi and Behar, 2011; Scanga et al., 2000).”
Selwyn, P. A., Hartel, D. M., Lewis, V. A., Schoenbaum, E. E., Vermund, S. H., Klein, R. S., Walker, A. T., & FRIEDLAND, G. H. (1989) · New England Journal of Medicine · doi:10.1056/nejm198903023200901 · Cited by 1,572 · cited 1×
“In human disease, progressive CD4 T cell loss due to HIV infection also increases the risk for TB disease and death (Pawlowski et al., 2012; Selwyn et al., 1989).”
Nutritional immunity: transition metals at the pathogen–host interface
Hood, M. I., & Skaar, E. P. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2836 · Cited by 1,535 · cited 1×
“Infection triggers host responses that sequester important compounds such as amino acids and iron (Hood and Skaar, 2012; Zhang and Rubin, 2013).”
McKinney, J. D., zu Bentrup, K. H., Muñoz‐Elías, E. J., Miczák, A., Chen, B., Chan, W.-T., Swenson, D. L., Sacchettini, J. C., Jacobs, W. R., & Russell, D. G. (2000) · Nature · doi:10.1038/35021074 · Cited by 1,361 · cited 2×
“Mtb in particular relies upon cholesterol and fatty acid catabolism, gluconeogenesis, and the glyoxylate shunt to survive the host environment (Lee et al., 2013; Marrero et al., 2010; McKinney et al., 2000; Muñoz-Elı́as and McKinney, 2005; Pandey and Sassetti, 2008).”
Self-citationGenetic requirements for mycobacterial survival during infection
Sassetti, C. M., & Rubin, E. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2134250100 · Cited by 1,327 · cited 2×
“01), it also includes more than 400 newly discovered genes required for in vivo growth (Figure S2A) (Sassetti and Rubin, 2003).”
InfluentialSelf-citationGlobal tuberculosis control 2010
Behera, D. (2012) · The Indian Journal of Medical Research · Cited by 1,262
Cited by
Sorted by citations
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
“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
Macrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989
“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 454
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
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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