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The mycobacterial cell envelope — a moving target

Nature Reviews Microbiology volume 18, pages 47–59 (2020)Cite this article

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Abstract

Mycobacterium tuberculosis, the leading cause of death due to infection, has a dynamic and immunomodulatory cell envelope. The cell envelope structurally and functionally varies across the length of the cell and during the infection process. This variability allows the bacterium to manipulate the human immune system, tolerate antibiotic treatment and adapt to the variable host environment. Much of what we know about the mycobacterial cell envelope has been gleaned from model actinobacterial species, or model conditions such as growth in vitro, in macrophages and in the mouse. In this Review, we combine data from different experimental systems to build a model of the dynamics of the mycobacterial cell envelope across space and time. We describe the regulatory pathways that control metabolism of the cell wall and surface lipids in M. tuberculosis during growth and stasis, and speculate about how this regulation might affect antibiotic susceptibility and interactions with the immune system.

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Fig. 1: Model of the mycobacterial cell envelope.
Fig. 2: The cell envelope of Mycobacterium tuberculosis during active growth and growth stasis.
Fig. 3: Regulation of arabinogalactan and surface lipids in active growth and growth stasis.
Fig. 4: Regulation of peptidoglycan in active growth and growth stasis.
Fig. 5: Regulation of mycolic acids and trehalose mycolates in active growth and growth stasis.

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References

  1. Cambier, C. J., Falkow, S. & Ramakrishnan, L. Host evasion and exploitation schemes of Mycobacterium tuberculosis. Cell 159, 1497–1509 (2014).

    CAS  PubMed  Google Scholar 

  2. Lin, P. L. et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat. Med. 20, 75–79 (2014). This transformational article shows that human infections are variable at the level of the granuloma, with each granuloma progressing separately.

    CAS  PubMed  Google Scholar 

  3. Gideon, H. P. et al. Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization. PLOS Pathog. 11, e1004603 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. Malherbe, S. T. et al. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nat. Med. 22, 1094–1100 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Chiaradia, L. et al. Dissecting the mycobacterial cell envelope and defining the composition of the native mycomembrane. Sci. Rep. 7, 12807 (2017).

    PubMed  PubMed Central  Google Scholar 

  6. Hoffmann, C., Leis, A., Niederweis, M., Plitzko, J. M. & Engelhardt, H. Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc. Natl Acad. Sci. USA 105, 3963–3967 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Zuber, B. et al. Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J. Bacteriol. 190, 5672–5680 (2008). This study and Hoffmann et al. (2008) produce the first high resolution cryogenic electron microscopy datasets that verify the existence of the mycobacterial outer membrane (the mycomembrane) and the spatial organization of the other envelope layers.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Minnikin, D. E. et al. Pathophysiological implications of cell envelope structure in Mycobacterium tuberculosis and related taxa. in Tuberculosis - Expanding Knowl. (ed. Ribon, W.) (InTech, 2015). https://doi.org/10.5772/59585

  9. Daffé, M. & Etienne, G. The capsule of Mycobacterium tuberculosis and its implications for pathogenicity. Tuber. Lung Dis. 79, 153–169 (1999).

    PubMed  Google Scholar 

  10. Manganelli, R. Sigma factors: key molecules in Mycobacterium tuberculosis physiology and virulence. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.MGM2-0007-2013 (2014).

  11. Parish, T. Two-component regulatory systems of mycobacteria. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.MGM2-0010-2013 (2014).

  12. Prisic, S. & Husson, R. N. Mycobacterium tuberculosis serine/threonine protein kinases. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.MGM2-0006-2013 (2014).

  13. Xi, X., Han, X., Li, L. & Zhao, Z. Identification of a new tuberculosis antigen recognized by γδ t cell receptor. Clin. Vaccine Immunol. 20, 530–539 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bacon, J. et al. Non-replicating Mycobacterium tuberculosis elicits a reduced infectivity profile with corresponding modifications to the cell wall and extracellular matrix. PLOS ONE 9, e87329 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. Sarathy, J., Dartois, V., Dick, T. & Gengenbacher, M. Reduced drug uptake in phenotypically resistant nutrient-starved nonreplicating Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 57, 1648–1653 (2013). This article is the first to show what has long been suspected — that cells in stasis are less permeable to antibiotics.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Seiler, P. et al. Cell-wall alterations as an attribute of Mycobacterium tuberculosis in latent infection. J. Infect. Dis. 188, 1326–1331 (2003). This observational study with human and mouse tissue sections shows that M. tuberculosis cells in latent infection have a cell wall that is different from that observed during active infection.

    PubMed  Google Scholar 

  17. Xie, Z., Siddiqi, N. & Rubin, E. J. Differential antibiotic susceptibilities of starved Mycobacterium tuberculosis isolates. Antimicrob. Agents Chemother. 49, 4778–4780 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Xu, W. et al. Chemical genetic interaction profiling reveals determinants of intrinsic antibiotic resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 61, e01334-17 (2017).

    PubMed  PubMed Central  Google Scholar 

  19. Alderwick, L. J., Harrison, J., Lloyd, G. S. & Birch, H. L. The mycobacterial cell wall—peptidoglycan and arabinogalactan. Cold Spring Harb. Perspect. Med. 5, (2015).

  20. Guerin, M. E., Korduláková, J., Alzari, P. M., Brennan, P. J. & Jackson, M. Molecular basis of phosphatidyl-myo-inositol mannoside biosynthesis and regulation in mycobacteria. J. Biol. Chem. 285, 33577–33583 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Marrakchi, H., Lanéelle, M.-A. & Daffé, M. Mycolic acids: structures, biosynthesis, and beyond. Chem. & Biol. 21, 67–85 (2014).

    CAS  Google Scholar 

  22. Mishra, A. K., Driessen, N. N., Appelmelk, B. J. & Besra, G. S. Lipoarabinomannan and related glycoconjugates: structure, biogenesis and role in Mycobacterium tuberculosis physiology and host–pathogen interaction. FEMS Microbiol. Rev. 35, 1126–1157 (2011).

    CAS  PubMed  Google Scholar 

  23. Brennan, P. J. & Nikaido, H. The envelope of mycobacteria. Annu. Rev. Biochem. 64, 29–63 (1995).

    CAS  PubMed  Google Scholar 

  24. Cook, G. M. et al. Physiology of mycobacteria. Adv. Microb. Physiol. 55, 81–319 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kieser, K. J. & Rubin, E. J. How sisters grow apart: mycobacterial growth and division. Nat. Rev. Microbiol. 12, 550–562 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Aldridge, B. B. et al. Asymmetry and aging of mycobacterial cells leads to variable growth and antibiotic susceptibility. Science 335, 100–104 (2012).

    CAS  PubMed  Google Scholar 

  27. Santi, I., Dhar, N., Bousbaine, D., Wakamoto, Y. & McKinney, J. D. Single-cell dynamics of the chromosome replication and cell division cycles in mycobacteria. Nat. Commun. 4, 2470 (2013).

    PubMed  Google Scholar 

  28. Hayashi, J. M. et al. Spatially distinct and metabolically active membrane domain in mycobacteria. Proc. Natl Acad. Sci. USA 113, 5400–5405 (2016). This article demonstrates, for the first time, the existence of an organelle in mycobacteria, that appears to be important for synthesis of the cell wall.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Jani, C. et al. Regulation of polar peptidoglycan biosynthesis by Wag31 phosphorylation in mycobacteria. BMC Microbiol. 10, 327 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kang, C.-M., Nyayapathy, S., Lee, J.-Y., Suh, J.-W. & Husson, R. N. Wag31, a homologue of the cell division protein DivIVA, regulates growth, morphology and polar cell wall synthesis in mycobacteria. Microbiology 154, 725–735 (2008).

    CAS  PubMed  Google Scholar 

  31. Meniche, X. et al. Subpolar addition of new cell wall is directed by DivIVA in mycobacteria. Proc. Natl Acad. Sci. USA 111, E3243–E3251 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Baer, C. E., Iavarone, A. T., Alber, T. & Sassetti, C. M. Biochemical and spatial coincidence in the provisional Ser/Thr protein kinase interaction network of Mycobacterium tuberculosis. J. Biol. Chem. 289, 20422–20433 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Botella, H. et al. Distinct spatiotemporal dynamics of peptidoglycan synthesis between Mycobacterium smegmatis and Mycobacterium tuberculosis. mBio 8, e01183-17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kuru, E., Tekkam, S., Hall, E., Brun, Y. V. & Van Nieuwenhze, M. S. Synthesis of fluorescent d-amino acids and their use for probing peptidoglycan synthesis and bacterial growth in situ. Nat. Protoc. 10, 33–52 (2015).

    CAS  PubMed  Google Scholar 

  35. Thanky, N. R., Young, D. B. & Robertson, B. D. Unusual features of the cell cycle in mycobacteria: polar-restricted growth and the snapping-model of cell division. Tuberculosis 87, 231–236 (2007).

    CAS  PubMed  Google Scholar 

  36. Baranowski, C. et al. Maturing Mycobacterium smegmatis peptidoglycan requires non-canonical crosslinks to maintain shape. eLife 7, e37516 (2018). This article makes a strong argument, through meticulous though necessarily indirect experiments, that the chemical structure of peptidoglycan varies across the length of the cell.

    PubMed  PubMed Central  Google Scholar 

  37. Carel, C. et al. Mycobacterium tuberculosis proteins involved in mycolic acid synthesis and transport localize dynamically to the old growing pole and septum. PLOS ONE 9, e97148 (2014).

    PubMed  PubMed Central  Google Scholar 

  38. Hodges, H. L., Brown, R. A., Crooks, J. A., Weibel, D. B. & Kiessling, L. L. Imaging mycobacterial growth and division with a fluorogenic probe. Proc. Natl Acad. Sci. USA 115, 5271–5276 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhou, X. et al. Sequential assembly of the septal cell envelope prior to V snapping in Corynebacterium glutamicum. Nat. Chem. Biol. 15, 221 (2019). This thorough article shows that the cell wall core is assembled in an ordered fashion: the peptidoglycan layer is constructed before the mycolic acid layer (see Supplementary information for the mycobacterial data).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Rego, E. H., Audette, R. E. & Rubin, E. J. Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity. Nature 546, 153–157 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Eskandarian, H. A. et al. Division site selection linked to inherited cell surface wave troughs in mycobacteria. Nat. Microbiol. 2, 17094 (2017).

    CAS  PubMed  Google Scholar 

  42. Joyce, G. et al. Cell division site placement and asymmetric growth in mycobacteria. PLOS ONE 7, e44582 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Singh, B. et al. Asymmetric growth and division in Mycobacterium spp.: compensatory mechanisms for non-medial septa. Mol. Microbiol. 88, 64–76 (2013).

    CAS  PubMed  Google Scholar 

  44. Wu, M.-L., Gengenbacher, M. & Dick, T. Mild nutrient starvation triggers the development of a small-cell survival morphotype in mycobacteria. Front. Microbiol. 7, (2016).

  45. Hayashi, J. M. et al. Stress-induced reorganization of the mycobacterial membrane domain. mBio 9, e01823-17 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. Gill, W. P. et al. A replication clock for Mycobacterium tuberculosis. Nat. Med. 15, 211–214 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ford, C. B. et al. Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat. Genet. 43, 482–486 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang, Y. J. et al. Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Cell 155, 1296–1308 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Wayne, L. G. & Hayes, L. G. An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect. Immun. 64, 8 (1996).

    Google Scholar 

  50. Bansal-Mutalik, R. & Nikaido, H. Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides. Proc. Natl Acad. Sci. USA 111, 4958–4963 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Fukuda, T. et al. Critical roles for lipomannan and lipoarabinomannan in cell wall integrity of mycobacteria and pathogenesis of tuberculosis. mBio 4, e00472-12 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Koul, A., Herget, T., Klebl, B. & Ullrich, A. Interplay between mycobacteria and host signalling pathways. Nat. Reviews Microbiol. 2, 189–202 (2004).

    CAS  Google Scholar 

  53. Glass, L. N. et al. Mycobacterium tuberculosis universal stress protein Rv2623 interacts with the putative ATP binding cassette (ABC) transporter Rv1747 to regulate mycobacterial growth. PLOS Pathog. 13, e1006515 (2017).

    PubMed  PubMed Central  Google Scholar 

  54. Crellin, P. K. et al. Mutations in pime restore lipoarabinomannan synthesis and growth in a Mycobacterium smegmatis IpqW mutant. J. Bacteriol. 190, 3690–3699 (2008). This article describes the genetic mechanisms by which the PIM and LAM lipids, despite being biosynthetically linked, can be differentially regulated.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Drumm, J. E. et al. Mycobacterium tuberculosis universal stress protein Rv2623 regulates bacillary growth by ATP-binding: requirement for establishing chronic persistent infection. PLOS Pathog. 5, e1000460 (2009).

    PubMed  PubMed Central  Google Scholar 

  56. Pang, X. et al. Evidence for complex interactions of stress-associated regulons in an mprAB deletion mutant of Mycobacterium tuberculosis. Microbiology 153, 1229–1242 (2007).

    CAS  PubMed  Google Scholar 

  57. Rustad, T. R., Harrell, M. I., Liao, R. & Sherman, D. R. The enduring hypoxic response of Mycobacterium tuberculosis. PLOS ONE 3, e1502 (2008).

    PubMed  PubMed Central  Google Scholar 

  58. Nigou, J. et al. Mannan chain length controls lipoglycans signaling via and binding to TLR2. J. Immunol. 180, 6696–6702 (2008).

    CAS  PubMed  Google Scholar 

  59. Betts, J. C., Lukey, P. T., Robb, L. C., McAdam, R. A. & Duncan, K. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol. Microbiol. 43, 717–731 (2002).

    CAS  PubMed  Google Scholar 

  60. Peterson, E. J. et al. Path-seq identifies an essential mycolate remodeling program for mycobacterial host adaptation. Mol. Syst. Biol. 15, e8584 (2019).

    PubMed  PubMed Central  Google Scholar 

  61. Papavinasasundaram, K. G. et al. Deletion of the Mycobacterium tuberculosis pknH gene confers a higher bacillary load during the chronic phase of infection in BALB/c mice. J. Bacteriol. 187, 5751–5760 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Harding, C. V. & Boom, W. H. Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors. Nat. Rev. Microbiol. 8, 296–307 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Petit, J. F., Adam, A., Wietzerbin-Falszpan, J., Lederer, E. & Ghuysen, J.-M. Chemical structure of the cell wall of Mycobacterium smegmatis. I. Isolation and partial characterization of the peptidoglycan. Biochem. Biophys. Res. Commun. 35, 478–485 (1969).

    CAS  PubMed  Google Scholar 

  64. Meroueh, S. O. et al. Three-dimensional structure of the bacterial cell wall peptidoglycan. Proc. Natl Acad. Sci. USA 103, 4404–4409 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Carette, X. et al. Multisystem analysis of Mycobacterium tuberculosis reveals kinase-dependent remodeling of the pathogen-environment interface. mBio 9, (2018).

  66. Kaur, P. et al. LipidII interaction with specific residues of Mycobacterium tuberculosis PknB extracytoplasmic domain governs its optimal activation. Nat. Commun. 10, 1231 (2019). This article identifies the upstream molecular signal that controls an important regulator.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Boutte, C. C. et al. A cytoplasmic peptidoglycan amidase homologue controls mycobacterial cell wall synthesis. eLife 5, e14590 (2016).

    PubMed  PubMed Central  Google Scholar 

  68. Turapov, O. et al. Two faces of CwlM, an essential PknB substrate, in Mycobacterium tuberculosis. Cell Rep. 25, 57–67 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Gee, C. L. et al. A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria. Sci. Signal. 5, ra7 (2012).

    PubMed  PubMed Central  Google Scholar 

  70. Kieser, K. J. et al. Phosphorylation of the peptidoglycan synthase PonA1 governs the rate of polar elongation in mycobacteria. PLOS Pathog. 11, e1005010 (2015).

    PubMed  PubMed Central  Google Scholar 

  71. Kang, C.-M. The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape. Genes Dev. 19, 1692–1704 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Ortega, C. et al. Mycobacterium tuberculosis Ser/Thr protein kinase B mediates an oxygen-dependent replication switch. PLoS Biol. 12, e1001746 (2014). This article describes a complete cycle of growth, stasis and reactivation, and shows how the critical cell wall regulator, PknB, plays a key role in each stage.

    PubMed  PubMed Central  Google Scholar 

  73. Fontán, P. A. et al. The Mycobacterium tuberculosis sigma factor σB is required for full response to cell envelope stress and hypoxia in vitro, but it is dispensable for in vivo growth. J. Bacteriol. 191, 5628–5633 (2009).

    PubMed  PubMed Central  Google Scholar 

  74. Kieser, K. J. et al. Peptidoglycan synthesis in Mycobacterium tuberculosis is organized into networks with varying drug susceptibility. Proc. Natl Acad. Sci. USA 112, 13087–13092 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Kumar, P. et al. Meropenem inhibits D,D-carboxypeptidase activity in Mycobacterium tuberculosis. Mol. Microbiol. 86, 367–381 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Behr, M. A. & Divangahi, M. Freund’s adjuvant, NOD2 and mycobacteria. Curr. Opin. Microbiol. 23, 126–132 (2015).

    CAS  PubMed  Google Scholar 

  77. Deng, J. et al. Mycobacterium tuberculosis proteome microarray for global studies of protein function and immunogenicity. Cell Rep. 9, 2317–2329 (2014).

    CAS  PubMed  Google Scholar 

  78. Khan, M. Z. et al. Protein kinase G confers survival advantage to Mycobacterium tuberculosis during latency-like conditions. J. Biol. Chem. 292, 16093–16108 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Escuyer, V. E. et al. The role of the emba and embb gene products in the biosynthesis of the terminal hexaarabinofuranosyl motif of Mycobacterium smegmatis arabinogalactan. J. Biol. Chem. 276, 48854–48862 (2001).

    CAS  PubMed  Google Scholar 

  80. Zhang, N. et al. The Emb proteins of mycobacteria direct arabinosylation of lipoarabinomannan and arabinogalactan via an N-terminal recognition region and a C-terminal synthetic region. Mol. Microbiol. 50, 69–76 (2003).

    CAS  PubMed  Google Scholar 

  81. Sharma, K. et al. Transcriptional control of the mycobacterial embCAB operon by PknH through a regulatory protein, EmbR, in vivo. J. Bacteriol. 188, 2936–2944 (2006). This article is one of the first to describe an entire regulatory pathway that controls cell wall metabolism, and to show how it affects antibiotic susceptibility.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Williams, E. P., Lee, J.-H., Bishai, W. R., Colantuoni, C. & Karakousis, P. C. Mycobacterium tuberculosis SigF regulates genes encoding cell wall-associated proteins and directly regulates the transcriptional regulatory gene phoY1. J. Bacteriol. 189, 4234–4242 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hatzios, S. K. et al. Osmosensory signaling in Mycobacterium tuberculosis mediated by a eukaryotic-like Ser/Thr protein kinase. Proc. Natl Acad. Sci. USA 110, E5069–E5077 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Chen, P., Ruiz, R. E., Li, Q., Silver, R. F. & Bishai, W. R. Construction and characterization of a Mycobacterium tuberculosis mutant lacking the alternate sigma factor gene, sigF. Infect. Immun. 68, 5575–5580 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Sharma, K., Gupta, M., Krupa, A., Srinivasan, N. & Singh, Y. EmbR, a regulatory protein with ATPase activity, is a substrate of multiple serine/threonine kinases and phosphatase in Mycobacterium tuberculosis. FEBS J. 273, 2711–2721 (2006).

    CAS  PubMed  Google Scholar 

  86. Molle, V. et al. An FHA phosphoprotein recognition domain mediates protein EmbR phosphorylation by PknH, a Ser/Thr protein kinase from Mycobacterium tuberculosis. Biochem. 42, 15300–15309 (2003).

    CAS  Google Scholar 

  87. Jarlier, V. & Nikaido, H. Permeability barrier to hydrophilic solutes in Mycobacterium chelonei. J. Bacteriol. 172, 1418–1423 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Dahl, J. L. et al. The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proc. Natl Acad. Sci. USA 100, 10026–10031 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Molle, V., Brown, A. K., Besra, G. S., Cozzone, A. J. & Kremer, L. The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation. J. Biol. Chem. 281, 30094–30103 (2006).

    CAS  PubMed  Google Scholar 

  90. Vilchèze, C. et al. Phosphorylation of KasB regulates virulence and acid-fastness in Mycobacterium tuberculosis. PLOS Pathog. 10, e1004115 (2014).

    PubMed  PubMed Central  Google Scholar 

  91. Slama, N. et al. Negative regulation by Ser/Thr phosphorylation of HadAB and HadBC dehydratases from Mycobacterium tuberculosis type II fatty acid synthase system. Biochem. Biophys. Res. Commun. 412, 401–406 (2011).

    CAS  PubMed  Google Scholar 

  92. Khan, S. et al. Phosphorylation of enoyl-acyl carrier protein reductase inha impacts mycobacterial growth and survival. J. Biol. Chem. 285, 37860–37871 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Veyron-Churlet, R., Zanella-Cléon, I., Cohen-Gonsaud, M., Molle, V. & Kremer, L. Phosphorylation of the Mycobacterium tuberculosis β-ketoacyl-acyl carrier protein reductase MabA regulates mycolic acid biosynthesis. J. Biol. Chem. 285, 12714–12725 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Deol, P. et al. Role of Mycobacterium tuberculosis Ser/Thr kinase PknF: implications in glucose transport and cell division. J. Bacteriol. 187, 3415–3420 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Refaya, A. K., Sharma, D., Kumar, V., Bisht, D. & Narayanan, S. A serine/threonine kinase PknL, is involved in the adaptive response of Mycobacterium tuberculosis. Microbiol. Res. 190, 1–11 (2016).

    PubMed  Google Scholar 

  96. Corrales, R. M. et al. Phosphorylation of mycobacterial PcaA inhibits mycolic acid cyclopropanation: consequences for intracellular survival and for phagosome maturation block. J. Biol. Chem. 287, 26187–26199 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Rao, V., Fujiwara, N., Porcelli, S. A. & Glickman, M. S. Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule. J. Exp. Med. 201, 535–543 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Dubnau, E. et al. Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol. Microbiol. 36, 630–637 (2000).

    CAS  PubMed  Google Scholar 

  99. Sambandan, D. et al. Keto-mycolic acid-dependent pellicle formation confers tolerance to drug-sensitive Mycobacterium tuberculosis. mBio 4, e00222-13 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Rao, V. Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis-induced inflammation and virulence. J. Clin. Invest. 116, 1660–1667 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Churchyard, G. J. et al. A trial of mass isoniazid preventive therapy for tuberculosis control. N. Engl. J. Med. 370, 301–310 (2014).

    CAS  PubMed  Google Scholar 

  102. Belisle, J. T. et al. Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science 276, 1420–1422 (1997).

    CAS  PubMed  Google Scholar 

  103. Puech, V. et al. Evidence for a partial redundancy of the fibronectin-binding proteins for the transfer of mycoloyl residues onto the cell wall arabinogalactan termini of Mycobacterium tuberculosis. Mol. Microbiol. 44, 1109–1122 (2002).

    CAS  PubMed  Google Scholar 

  104. Jackson, M. et al. Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope. Mol. Microbiol. 31, 1573–1587 (1999).

    CAS  PubMed  Google Scholar 

  105. Nguyen, L., Chinnapapagari, S. & Thompson, C. J. FbpA-dependent biosynthesis of trehalose dimycolate is required for the intrinsic multidrug resistance, cell wall structure, and colonial morphology of Mycobacterium smegmatis. J. Bacteriol. 187, 6603–6611 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Wilkinson, R. J. et al. An increase in expression of a Mycobacterium tuberculosis mycolyl transferase gene (fbpB) occurs early after infection of human monocytes. Mol. Microbiol. 39, 813–821 (2001).

    CAS  PubMed  Google Scholar 

  107. Eoh, H. et al. Metabolic anticipation in Mycobacterium tuberculosis. Nat. Microbiol. 2, (2017).

  108. Galagan, J. E. et al. The Mycobacterium tuberculosis regulatory network and hypoxia. Nature 499, 178–183 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Armitige, L. Y., Jagannath, C., Wanger, A. R. & Norris, S. J. Disruption of the genes encoding antigen 85a and antigen 85b of Mycobacterium tuberculosis H37Rv: effect on growth in culture and in macrophages. Infect. Immun. 68, 767–778 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Hunter, R. L., Olsen, M. R., Jagannath, C. & Actor, J. K. Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease. Ann. Clin. Lab Sci. 36, 371–386 (2006).

    CAS  PubMed  Google Scholar 

  111. Lee, J. J. et al. Transient drug-tolerance and permanent drug-resistance rely on the trehalose-catalytic shift in Mycobacterium tuberculosis. Nat. Commun. 10, 2928 (2019).

    PubMed  PubMed Central  Google Scholar 

  112. Cambier, C. J. et al. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505, 218–222 (2014).

    CAS  PubMed  Google Scholar 

  113. Barczak, A. K. et al. Systematic, multiparametric analysis of Mycobacterium tuberculosis intracellular infection offers insight into coordinated virulence. PLOS Pathog. 13, e1006363 (2017).

    PubMed  PubMed Central  Google Scholar 

  114. Quigley, J. et al. The cell wall lipid PDIM contributes to phagosomal escape and host cell exit of Mycobacterium tuberculosis. mBio 8, e00148-17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Schubert, O. T. et al. Absolute proteome composition and dynamics during dormancy and resuscitation of Mycobacterium tuberculosis. Cell Host Microbe 18, 96–108 (2015).

    CAS  PubMed  Google Scholar 

  116. Falkinham, J. O. Mycobacterial aerosols and respiratory disease. Emerg. Infect. Dis. 9, 763–767 (2003).

    PubMed  PubMed Central  Google Scholar 

  117. Ehrt, S. & Schnappinger, D. Mycobacterial survival strategies in the phagosome: defence against host stresses. Cell Microbiol. 11, 1170–1178 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Roy, S. et al. Molecular basis of mycobacterial lipid antigen presentation by CD1c and its recognition by αβ T cells. Proc. Natl Acad. Sci. USA 111, E4648–E4657 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Chancellor, A. et al. CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains. Proc. Natl Acad. Sci. USA 114, E10956–E10964 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Moody, D. B. et al. Cd1b-Mediated T cell recognition of a glycolipid antigen generated from mycobacterial lipid and host carbohydrate during infection. J. Exp. Med. 192, 965–976 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Gilleron, M. et al. Diacylated sulfoglycolipids are novel mycobacterial antigens stimulating CD1-restricted T cells during infection with Mycobacterium tuberculosis. J. Exp. Med. 199, 649–659 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Busch, M. et al. Lipoarabinomannan-responsive polycytotoxic T cells are associated with protection in human tuberculosis. Am. J. Respir. Crit. Care Med. 194, 345–355 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Ernst, W. A. et al. Molecular interaction of CD1b with lipoglycan antigens. Immunity 8, 331–340 (1998).

    CAS  PubMed  Google Scholar 

  124. Janis, E. M., Kaufmann, S. H., Schwartz, R. H. & Pardoll, D. M. Activation of gamma delta T cells in the primary immune response to Mycobacterium tuberculosis. Science 244, 713–716 (1989).

    CAS  PubMed  Google Scholar 

  125. Van Rhijn, I. et al. A conserved human T cell population targets mycobacterial antigens presented by CD1b. Nat. Immunol. 14, 706–713 (2013).

    PubMed  PubMed Central  Google Scholar 

  126. O’Garra, A. et al. The immune response in tuberculosis. Annu. Rev. Immunol. 31, 475–527 (2013).

    PubMed  Google Scholar 

  127. Roy, A. et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ 349, g4643 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Maglione, P. J. & Chan, J. How B cells shape the immune response against Mycobacterium tuberculosis. Eur. J. Immunol. 39, 676–686 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Blanc, L. et al. Mycobacterium tuberculosis inhibits human innate immune responses via the production of TLR2 antagonist glycolipids. Proc. Natl Acad. Sci. USA 114, 11205–11210 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Tobian, A. A. R. et al. Alternate class I MHC antigen processing is inhibited by Toll-like receptor signaling pathogen-associated molecular patterns: Mycobacterium tuberculosis 19-kDa lipoprotein, CpG DNA, and lipopolysaccharide. J. Immunol. 171, 1413–1422 (2003).

    CAS  PubMed  Google Scholar 

  131. Koh, K. W., Lehming, N. & Seah, G. T. Degradation-resistant protein domains limit host cell processing and immune detection of mycobacteria. Mol. Immunol. 46, 1312–1318 (2009).

    CAS  PubMed  Google Scholar 

  132. Saini, N. K. et al. Suppression of autophagy and antigen presentation by Mycobacterium tuberculosis PE_PGRS47. Nat. Microbiol. 1, 16133 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Gagliardi, M. C. et al. Cell wall-associated alpha-glucan is instrumental for Mycobacterium tuberculosis to block CD1 molecule expression and disable the function of dendritic cell derived from infected monocyte. Cell Microbiol. 9, 2081–2092 (2007).

    CAS  PubMed  Google Scholar 

  134. Stenger, S., Niazi, K. R. & Modlin, R. L. Down-regulation of CD1 on antigen-presenting cells by infection with Mycobacterium tuberculosis. J. Immunol. 161, 3582–3588 (1998).

    CAS  PubMed  Google Scholar 

  135. Houben, D. et al. ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria. Cell Microbiol. 14, 1287–1298 (2012).

    CAS  PubMed  Google Scholar 

  136. van der Wel, N. et al. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129, 1287–1298 (2007).

    PubMed  Google Scholar 

  137. Conrad, W. H. et al. Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions. Proc. Natl Acad. Sci. USA 114, 1371–1376 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Solomonson, M. et al. Structure of EspB from the ESX-1 type VII secretion system and insights into its export mechanism. Structure 23, 571–583 (2015).

    CAS  PubMed  Google Scholar 

  139. MacGurn, J. A. & Cox, J. S. A genetic screen for Mycobacterium tuberculosis mutants defective for phagosome maturation arrest identifies components of the ESX-1 secretion system. Infect. Immun. 75, 2668–2678 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Portal-Celhay, C. et al. Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation. Nat. Microbiol. 2, 16232 (2016).

    PubMed  PubMed Central  Google Scholar 

  141. Thi, E. P., Hong, C. J. H., Sanghera, G. & Reiner, N. E. Identification of the Mycobacterium tuberculosis protein PE-PGRS62 as a novel effector that functions to block phagosome maturation and inhibit iNOS expression. Cell Microbiol. 15, 795–808 (2013).

    CAS  PubMed  Google Scholar 

  142. Augenstreich, J. et al. ESX-1 and phthiocerol dimycocerosates of Mycobacterium tuberculosis act in concert to cause phagosomal rupture and host cell apoptosis. Cell Microbiol. 19, (2017).

  143. Rousseau, C. et al. Production of phthiocerol dimycocerosates protects Mycobacterium tuberculosis from the cidal activity of reactive nitrogen intermediates produced by macrophages and modulates the early immune response to infection. Cell Microbiol. 6, 277–287 (2004).

    CAS  PubMed  Google Scholar 

  144. Ishikawa, E. et al. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J. Exp. Med. 206, 2879–2888 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Geisel, R. E., Sakamoto, K., Russell, D. G. & Rhoades, E. R. In vivo activity of released cell wall lipids of Mycobacterium bovis bacillus Calmette-Guérin is due principally to trehalose mycolates. J. Immunol. 174, 5007–5015 (2005).

    CAS  PubMed  Google Scholar 

  146. Dubée, V. et al. Inactivation of Mycobacterium tuberculosis l,d-transpeptidase LdtMt1 by carbapenems and cephalosporins. Antimicrob. Agents Chemother. 56, 4189–4195 (2012).

    PubMed  PubMed Central  Google Scholar 

  147. Gupta, R. et al. The Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin. Nat. Med. 16, 466–469 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Goude, R., Amin, A. G., Chatterjee, D. & Parish, T. The arabinosyltransferase EmbC is inhibited by ethambutol in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 53, 4138–4146 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. de Steenwinkel, J. E. M. et al. Time–kill kinetics of anti-tuberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis. J. Antimicrob. Chemother. 65, 2582–2589 (2010).

    PubMed  Google Scholar 

  150. Makarov, V. et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324, 801–804 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Gao, C. et al. Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis. Sci. Rep. 6, 29717 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Ando, H. et al. Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis. Mol. Microbiol. 79, 1615–1628 (2011).

    CAS  PubMed  Google Scholar 

  153. Pym, A. S. et al. Regulation of catalase–peroxidase (KatG) expression, isoniazid sensitivity and virulence by furA of Mycobacterium tuberculosis. Mol. Microbiol. 40, 879–889 (2001).

    CAS  PubMed  Google Scholar 

  154. Stanley, S. A. et al. Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32. Proc. Natl Acad. Sci. USA 110, 11565–11570 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Xu, Z., Meshcheryakov, V. A., Poce, G. & Chng, S.-S. MmpL3 is the flippase for mycolic acids in mycobacteria. Proc. Natl Acad. Sci. USA 114, 7993–7998 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Poce, G. et al. Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. PLOS ONE 8, e56980 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Stec, J. et al. Indole-2-carboxamide-based MmpL3 inhibitors show exceptional antitubercular activity in an animal model of tuberculosis infection. J. Med. Chem. 59, 6232–6247 (2016).

    CAS  PubMed  Google Scholar 

  158. Li, W. et al. Therapeutic potential of the Mycobacterium tuberculosis mycolic acid transporter, MmpL3. Antimicrob. Agents Chemother. 60, 5198–5207 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Li, W. et al. Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 58, 6413–6423 (2014).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank P. Brennan for his guidance and suggestions, and S. Fortune and A. Carey for critical reading and feedback on the manuscript. C.C.B. is supported by grant 1R15GM131317_01 from the US National Institutes of Health. E.J.R. and C.L.D. are supported by grant U19 AI107774 from the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Harvard University, Boston, MA, USA

    Charles L. Dulberger

  2. Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Charles L. Dulberger & Eric J. Rubin

  3. Department of Microbiology, Harvard Medical School, Boston, MA, USA

    Eric J. Rubin

  4. Department of Biology, University of Texas at Arlington, Arlington, TX, USA

    Cara C. Boutte

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C.C.B. and C.L.D. wrote the manuscript and developed the figures. E.R.B. provided critical feedback and suggested changes.

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Glossary

Granuloma

A mass of tissue, typically formed in response to infection, inflammation or the presence of a foreign substance.

Aerosol transmission

Infection of susceptible individuals via pathogen-laden, airborne particles or droplets.

Mycobacterium smegmatis

A non-pathogenic, fast-growing mycobacterial species that is often used as a model for studying mycobacterial cell biology.

Subclinical infection

An infection in humans that contains live Mycobacterium tuberculosis cells but in which the patient exhibits no symptoms because the infection is contained by the immune system.

Transposon sequencing

A genetic approach for determining the essentiality of genes. It combines transposon insertion mutagenesis with deep sequencing.

MHC class II antigen presentation

A critical strategy used by the adaptive immune system to detect and respond to infection and other stresses. Antigen-presenting cells relay information to T cells via cell surface MHC class I and MHC class II protein complexes that present peptides from self and non-self proteins they have encountered.

Acid-fastness

The resistance of bacteria or other cell types to acid-based or ethanol-based decolorization methods used in laboratory staining procedures, such as the Gram stain. As the waxy mycolic acids render mycobacteria impervious to the Gram stain, Robert Koch and Paul Ehrlich developed acid-fast staining methods for identifying Mycobacterium tuberculosis in clinical samples.

Pathogen-associated molecular patterns

Highly conserved molecular signatures found in proteins, lipids and small molecules made by pathogens. The innate immune system has evolved protein-based machinery, such as the Toll-like receptor pathways, to detect and initiate immune responses to pathogen-associated molecular patterns.

Type I interferon

A large group of cytokines, signalling proteins, that allow immune cells to communicate and respond to bacterial and viral infections.

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Dulberger, C.L., Rubin, E.J. & Boutte, C.C. The mycobacterial cell envelope — a moving target. Nat Rev Microbiol 18, 47–59 (2020). https://doi.org/10.1038/s41579-019-0273-7

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