Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Architecture of the dynamic fungal cell wall

Nature Reviews Microbiology volume 21, pages 248–259 (2023)Cite this article

Subjects

Abstract

The fungal cell wall is essential for growth and survival, and is a key target for antifungal drugs and the immune system. The cell wall must be robust but flexible, protective and shielding yet porous to nutrients and membrane vesicles and receptive to exogenous signals. Most fungi have a common inner wall skeleton of chitin and β-glucans that functions as a flexible viscoelastic frame to which a more diverse set of outer cell wall polymers and glycosylated proteins are attached. Whereas the inner wall largely determines shape and strength, the outer wall confers properties of hydrophobicity, adhesiveness, and chemical and immunological heterogeneity. The spatial organization and dynamic regulation of the wall in response to prevailing growth conditions enable fungi to thrive within changing, diverse and often hostile environments. Understanding this architecture provides opportunities to develop diagnostics and drugs to combat life-threatening fungal infections.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The cell wall defines the shape of the fungus.
Fig. 2: Architecture of the fungal cell wall.
Fig. 3: From microstructure to nanostructure of the cell wall.

Similar content being viewed by others

References

  1. Verstrepen, K. J., Reynolds, T. B. & Fink, G. R. Origins of variation in the fungal cell surface. Nat. Rev. Microbiol. 2, 533–540 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. de Groot, P. W. et al. A genomic approach for the identification and classification of genes involved in cell wall formation and its regulation in Saccharomyces cerevisiae. Comp. Funct. Genomics 2, 124–142 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Polizeli, M. L., Pietro, R. C., Jorge, J. A. & Terenzi, H. F. Effects of cell wall deficiency on the synthesis of polysaccharide-degrading exoenzymes: a study on mycelial and wall-less phenotypes of the fz; sg; os-1 (‘slime’) triple mutant of Neurospora crassa. J. Gen. Microbiol. 136, 1463–1468 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Ene, I. V. et al. Cell wall remodeling enzymes modulate fungal cell wall elasticity and osmotic stress resistance. mBio 6, e00986 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Money, N. P. & Fischer, M. W. F. in Plant Relationships Vol. 5 (ed. Deising, H. B.) 115–133 (Springer, 2009).

  6. Davì, V. et al. Mechanosensation dynamically coordinates polar growth and cell wall assembly to promote cell survival. Dev. Cell 45, 170–182.e7 (2018). This report demonstrates that cell wall thickness fluctuates during cell growth and is regulated by a mechanosensitive homeostatic mechanism.

    Article  PubMed  Google Scholar 

  7. Veneault-Fourrey, C., Barooah, M., Egan, M., Wakley, G. & Talbot, N. J. Autophagic fungal cell death is necessary for infection by the rice blast fungus. Science 312, 580–583 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Howard, R. J., Ferrari, M. A., Roach, D. H. & Money, N. P. Penetration of hard substrates by a fungus employing enormous turgor pressures. Proc. Natl Acad. Sci. USA 88, 11281–11284 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Talbot, N. J. Appressoria. Curr. Biol. 29, R144–R146 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Berger, B. W. & Sallada, N. D. Hydrophobins: multifunctional biosurfactants for interface engineering. J. Biol. Eng. 13, 10 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wösten, H. A. B. Hydrophobins: multipurpose proteins. Annu. Rev. Microbiol. 55, 625–646 (2001).

    Article  PubMed  Google Scholar 

  12. Winandy, L., Schlebusch, O. & Fischer, R. Fungal hydrophobins render stones impermeable for water but keep them permeable for vapor. Sci. Rep. 9, 6264 (2019). This publication explores the biophysical properties of fungal cell wall hydrophobin layers and shows that they have remarkable breathable yet waterproof properties.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nehls, U. & Dietz, S. Fungal aquaporins: cellular functions and ecophysiological perspectives. Appl. Microbiol. Biotechnol. 98, 8835–8851 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Casadevall, A. et al. The capsule of Cryptococcus neoformans. Virulence 10, 822–831 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Tlalka, M., Fricker, M. & Watkinson, S. Imaging of long-distance α-aminoisobutyric acid translocation dynamics during resource capture by Serpula lacrymans. Appl. Environ. Microbiol. 74, 2700–2708 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Aguilar-Trigueros, C. A., Boddy, L., Rillig, M. C. & Fricker, M. D. Network traits predict ecological strategies in fungi. ISME Commun. 2, 2 (2022).

    Article  PubMed Central  Google Scholar 

  17. Lew, R. R. How does a hypha grow? The biophysics of pressurized growth in fungi. Nat. Rev. Microbiol. 9, 509–518 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Sudbery, P. E. Growth of Candida albicans hyphae. Nat. Rev. Microbiol. 9, 737–748 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Read, N. D. in Oxford Textbook of Medical Mycology Ch. 4 (eds Kibbler, K. C. et al.) 23–34 (Oxford Univ. Press, 2018).

  20. Grün, C. H. et al. The structure of cell wall α-glucan from fission yeast. Glycobiology 15, 245–257 (2005).

    Article  PubMed  Google Scholar 

  21. Ma, L. et al. Genome analysis of three Pneumocystis species reveals adaptation mechanisms to life exclusively in mammalian hosts. Nat. Commun. 7, 10740 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Muzzarelli, C. J. & Gooday, G. W. (eds). Chitin in Nature and Technology (Springer, 1986).

  23. Kanagawa, M. et al. Structural insights into recognition of triple-helical β-glucans by an insect fungal receptor. J. Biol. Chem. 286, 29158–29165 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu, Y. et al. Triple helix conformation of β-d-glucan from Ganoderma lucidum and effect of molecular weight on its immunostimulatory activity. Int. J. Biol. Macromol. 114, 1064–1070 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Lenardon, M. D., Whitton, R. K., Munro, C. A., Marshall, D. & Gow, N. A. R. Individual chitin synthase enzymes synthesize microfibrils of differing structure at specific locations in the Candida albicans cell wall. Mol. Microbiol. 66, 1164–1173 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fernando, L. D. et al. Structural polymorphism of chitin and chitosan in fungal cell walls from solid-state NMR and principal component analysis. Front. Mol. Biosci. 8, 727053 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Latgé, J. P. & Wang, T. Modern biophysics redefines our understanding of fungal cell wall structure, complexity, and dynamics. mBio 13, e0114522 (2022).

    Article  PubMed  Google Scholar 

  28. Orlean, P. & Funai, D. Priming and elongation of chitin chains: implications for chitin synthase mechanism. Cell Surf. 5, 100017 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. da Silva Dantas, A. et al. Crosstalk between the calcineurin and cell wall integrity pathways prevents chitin overexpression in Candida albicans. J. Cell Sci. 134, jcs258889 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gow, N. A. R. & Gooday, G. W. Ultrastructure of chitin in hyphae of Candida albicans and other dimorphic and mycelial fungi. Protoplasma 115, 52–58 (1983).

    Article  Google Scholar 

  31. Vermeulen, C. A. & Wessels, J. G. H. Ultrastructural differences between wall apices of growing and non-growing hyphae of Schizophyllum commune. Protoplasma 120, 123–131 (1984).

    Article  Google Scholar 

  32. Vermeulen, C. A. & Wessels, J. G. Chitin biosynthesis by a fungal membrane preparation. Evidence for a transient non-crystalline state of chitin. Eur. J. Biochem. 158, 411–415 (1986).

    Article  CAS  PubMed  Google Scholar 

  33. Lenardon, M. D., Sood, P., Dorfmueller, H. C., Brown, A. J. P. & Gow, N. A. R. Scalar nanostructure of the Candida albicans cell wall; a molecular, cellular and ultrastructural analysis and interpretation. Cell Surf. 6, 100047 (2020). This publication provides the first to-scale model of the C. albicans cell wall and includes a menu of icons which can be used to construct other bespoke cell wall models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Popolo, L., Gualtieri, T. & Ragni, E. The yeast cell-wall salvage pathway. Med. Mycol. 39, 111–121 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Kang, X. et al. Molecular architecture of fungal cell walls revealed by solid-state NMR. Nat. Commun. 9, 2747 (2018). This report utilizes solid-state nuclear magnetic resonance to demonstrate that chitin and α-1,3-glucan in the Aspergillus cell wall forms a hydrophobic scaffold which is surrounded by β-glucans and capped by glycoproteins and α-1,3-glucan.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Krol, P. Synthesis methods, chemical structures and phase structures of linear polyurethanes. Properties and applications of linear polyurethanes in polyurethane elastomers, copolymers and ionomers. Prog. Mater. Sci. 52, 915–1015 (2007).

    Article  CAS  Google Scholar 

  37. Bates, S. et al. Outer chain N-glycans are required for cell wall integrity and virulence of Candida albicans. J. Biol. Chem. 281, 90–98 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Walker, L. et al. The viscoelastic properties of the fungal cell wall allow traffic of AmBisome as intact liposome vesicles. mBio 9, e02383-17 (2018). This study demonstrates that intact AmBisome vesicles can carry non-elastic gold particle cargoes through the fungal cell wall.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ene, I. V. et al. Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen. Cell. Microbiol. 14, 1319–1335 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ene, I. V. et al. Carbon source-induced reprogramming of the cell wall proteome and secretome modulates the adherence and drug resistance of the fungal pathogen Candida albicans. Proteomics 12, 3164–3179 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ballou, E. R. et al. Lactate signalling regulates fungal β-glucan masking and immune evasion. Nat. Microbiol. 2, 16238 (2016). This study makes key observations that Candida cells ‘mask’ β-1,3-glucan when grown on lactate, demonstrating that metabolic adaptability makes Candida cells an immunological moving target.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pradhan, A. et al. Non-canonical signalling mediates changes in fungal cell wall PAMPs that drive immune evasion. Nat. Commun. 10, 5315 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Plaine, A. et al. Functional analysis of Candida albicans GPI-anchored proteins: roles in cell wall integrity and caspofungin sensitivity. Fungal Genet. Biol. 45, 1404–1414 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lopes-Bezerra, L. M. et al. Cell walls of the dimorphic fungal pathogens Sporothrix schenckii and Sporothrix brasiliensis exhibit bilaminate structures and sloughing of extensive and intact layers. PLoS Negl. Trop. Dis. 12, e0006169 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hobson, R. P. et al. Loss of cell wall mannosylphosphate in Candida albicans does not influence macrophage recognition. J. Biol. Chem. 279, 39628–39635 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Mora-Montes, H. M. et al. A multifunctional mannosyltransferase family in Candida albicans determines cell wall mannan structure and host–fungus interactions. J. Biol. Chem. 285, 12087–12095 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Trinel, P. A. et al. Candida albicans serotype B strains synthesize a serotype-specific phospholipomannan overexpressing a β-1,2-linked mannotriose. Mol. Microbiol. 58, 984–998 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Singleton, D. R., Masuoka, J. & Hazen, K. C. Surface hydrophobicity changes of two Candida albicans serotype B mnn4delta mutants. Eukaryot. Cell 4, 639–648 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Silva-Dias, A. et al. Adhesion, biofilm formation, cell surface hydrophobicity, and antifungal planktonic susceptibility: relationship among Candida spp. Front. Microbiol. 6, 205 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Wessels, J. G. H. Hydrophobins, unique fungal proteins. Mycologist 14, 153–159 (2000).

    Article  Google Scholar 

  51. Aimanianda, V. et al. Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature 460, 1117–1121 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Carrion, S. J. et al. The RodA hydrophobin on Aspergillus fumigatus spores masks dectin-1- and dectin-2-dependent responses and enhances fungal survival in vivo. J. Immunol. 191, 2581–2588 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Willaert, R. G. Adhesins of yeasts: protein structure and interactions. J. Fungi 4, 119 (2018).

    Article  CAS  Google Scholar 

  54. Staab, J. F., Bradway, S. D., Fidel, P. L. & Sundstrom, P. Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1. Science 283, 1535–1538 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Nobile, C. J., Nett, J. E., Andes, D. R. & Mitchell, A. P. Function of Candida albicans adhesin Hwp1 in biofilm formation. Eukaryot. Cell 5, 1604–1610 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Netea, M. G., Brown, G. D., Kullberg, B. J. & Gow, N. A. R. An integrated model of the recognition of Candida albicans by the innate immune system. Nat. Rev. Microbiol. 6, 67–78 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Vendele, I. et al. Mannan detecting C-type lectin receptor probes recognise immune epitopes with diverse chemical, spatial and phylogenetic heterogeneity in fungal cell walls. PLoS Pathog. 16, e1007927 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kumar, R., Breindel, C., Saraswat, D., Cullen, P. J. & Edgerton, M. Candida albicans Sap6 amyloid regions function in cellular aggregation and zinc binding, and contribute to zinc acquisition. Sci. Rep. 7, 2908 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Lipke, P. N., Klotz, S. A., Dufrene, Y. F., Jackson, D. N. & Garcia-Sherman, M. C. Amyloid-like β-aggregates as force-sensitive switches in fungal biofilms and infections. Microbiol. Mol. Biol. Rev. 82, e00035-17 (2018).

    Article  PubMed  Google Scholar 

  60. Speth, C., Rambach, G., Lass-Flörl, C., Howell, P. L. & Sheppard, D. C. Galactosaminogalactan (GAG) and its multiple roles in Aspergillus pathogenesis. Virulence 10, 976–983 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gravelat, F. N. et al. Aspergillus galactosaminogalactan mediates adherence to host constituents and conceals hyphal β-glucan from the immune system. PLoS Pathog. 9, e1003575 (2013). This paper demonstrates that an epimerase is required for GAG synthesis which mediates adhesion of Aspergillus to a range of surfaces and is essential for virulence.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nosanchuk, J. D., Stark, R. E. & Casadevall, A. Fungal melanin: what do we know about structure? Front. Microbiol. 6, 1463 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Liu, S., Youngchim, S., Zamith-Miranda, D. & Nosanchuk, J. D. Fungal melanin and the mammalian immune system. J. Fungi 7, 264 (2021).

    Article  CAS  Google Scholar 

  64. Casadevall, A., Cordero, R. J. B., Bryan, R., Nosanchuk, J. & Dadachova, E. Melanin, radiation, and energy transduction in fungi. Microbiol. Spectr. 5, 5.2.05 (2017). This work proposes that fungal cell wall melanin can harness electromagnetic radiation as an energy source to promote survival.

    Article  Google Scholar 

  65. De Nobel, J. G., Dijkers, C., Hooijberg, E. & Klis, F. M. Increased cell wall porosity in Saccharomyces cerevisiae after treatment with dithiothreitol or EDTA. Microbiology 135, 2077–2084 (1989).

    Article  Google Scholar 

  66. Yadav, B. et al. Differences in fungal immune recognition by monocytes and macrophages: N-mannan can be a shield or activator of immune recognition. Cell Surf. 6, 100042 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Nazik, H. et al. Pseudomonas phage inhibition of Candida albicans. Microbiology 163, 1568–1577 (2017).

    Article  CAS  PubMed  Google Scholar 

  68. Nuss, D. L. Hypovirulence: mycoviruses at the fungal–plant interface. Nat. Rev. Microbiol. 3, 632–642 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Kim, Y. & Mylonakis, E. Killing of Candida albicans filaments by Salmonella enterica serovar Typhimurium is mediated by sopB effectors, parts of a type III secretion system. Eukaryot. Cell 10, 782–790 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Trunk, K. et al. The type VI secretion system deploys antifungal effectors against microbial competitors. Nat. Microbiol. 3, 920–931 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cuskin, F. et al. Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism. Nature 517, 165–169 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhao, K. et al. Extracellular vesicles secreted by Saccharomyces cerevisiae are involved in cell wall remodelling. Commun. Biol. 2, 305 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Dawson, C. S. et al. Protein markers for Candida albicans EVs include claudin-like Sur7 family proteins. J. Extracell. Vesicles 9, 1750810 (2020).

    Article  CAS  PubMed  Google Scholar 

  74. Zarnowski, R. et al. Candida albicans biofilm-induced vesicles confer drug resistance through matrix biogenesis. PLoS Biol. 16, e2006872 (2018). This publication shows that ESCRT-defective mutants have reduced biofilms and increased sensitivity to fluconazole, demonstrating that ECVs are critical in extracellular matrix production.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Zhao, M. et al. Turbinmicin inhibits Candida biofilm growth by disrupting fungal vesicle-mediated trafficking. J. Clin. Invest. 131, e145123 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  76. He, B. et al. RNA-binding proteins contribute to small RNA loading in plant extracellular vesicles. Nat. Plants 7, 342–352 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sorgo, A. G., Heilmann, C. J., Brul, S., de Koster, C. G. & Klis, F. M. Beyond the wall: Candida albicans secret(e)s to survive. FEMS Microbiol. Lett. 338, 10–17 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Kenno, S. et al. Candida albicans factor H binding molecule Hgt1p — a low glucose-induced transmembrane protein is trafficked to the cell wall and impairs phagocytosis and killing by human neutrophils. Front. Microbiol. 9, 3319 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Urban, C. et al. The moonlighting protein Tsa1p is implicated in oxidative stress response and in cell wall biogenesis in Candida albicans. Mol. Microbiol. 57, 1318–1341 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Satala, D., Karkowska-Kuleta, J., Zelazna, A., Rapala-Kozik, M. & Kozik, A. Moonlighting proteins at the Candidal cell surface. Microorganisms 8, 1046 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Gow, N. A. R., Latge, J. P. & Munro, C. A. The fungal cell wall: structure, biosynthesis, and function. Microbiol. Spectr. 5, 5.3.01 (2017).

    Article  Google Scholar 

  82. Desai, J. V. Candida albicans hyphae: from growth initiation to invasion. J. Fungi 4, 10 (2018).

    Article  Google Scholar 

  83. Riquelme, M. et al. Fungal morphogenesis, from the polarized growth of hyphae to complex reproduction and infection structures. Microbiol. Mol. Biol. Rev. 82, e00068-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Arkowitz, R. A. & Bassilana, M. Recent advances in understanding Candida albicans hyphal growth. F1000Res 8, 700 (2019).

    Article  Google Scholar 

  85. Schuster, M. et al. Co-delivery of cell-wall-forming enzymes in the same vesicle for coordinated fungal cell wall formation. Nat. Microbiol. 1, 16149 (2016). This study shows that the Ustilago class V and class VII chitin synthases (chitin synthases with an N-terminal myosin motor-like domain) and β-1,3-glucan synthases are transported and co-secreted in the same vesicles and that the myosin motor-like domains play a key role in the secretory process.

    Article  CAS  PubMed  Google Scholar 

  86. Klis, F. M., de Groot, P. & Hellingwerf, K. Molecular organization of the cell wall of Candida albicans. Med. Mycol. 39, 1–8 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Garcia-Rubio, R., de Oliveira, H. C., Rivera, J. & Trevijano-Contador, N. The fungal cell wall: Candida, Cryptococcus, and Aspergillus species. Front. Microbiol. 10, 2993 (2019).

    Article  PubMed  Google Scholar 

  88. Yoshimi, A., Miyazawa, K. & Abe, K. Cell wall structure and biogenesis in Aspergillus species. Biosci. Biotechnol. Biochem. 80, 1700–1711 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Mazáň, M. et al. A novel fluorescence assay and catalytic properties of Crh1 and Crh2 yeast cell wall transglycosylases. Biochem. J. 455, 307–318 (2013).

    Article  PubMed  Google Scholar 

  90. Knafler, H. C. et al. AP-2-dependent endocytic recycling of the chitin synthase Chs3 regulates polarized growth in Candida albicans. mBio 10, e02421-18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Munro, C. A. et al. The PKC, HOG and Ca2+ signalling pathways co-ordinately regulate chitin synthesis in Candida albicans. Mol. Microbiol. 63, 1399–1413 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dichtl, K., Samantaray, S. & Wagener, J. Cell wall integrity signalling in human pathogenic fungi. Cell. Microbiol. 18, 1228–1238 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Ibe, C. & Munro, C. A. Fungal cell wall: an underexploited target for antifungal therapies. PLoS Pathog. 17, e1009470 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. González-Rubio, G., Fernández-Acero, T., Martín, H. & Molina, M. Mitogen-activated protein kinase phosphatases (MKPs) in fungal signaling: conservation, function, and regulation. Int. J. Mol. Sci. 20, 1709 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Walker, L. A. et al. Stimulation of chitin synthesis rescues Candida albicans from echinocandins. PLoS Pathog. 4, e1000040 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Shivarathri, R. et al. The two-component response regulator Ssk1 and the mitogen-activated protein kinase Hog1 control antifungal drug resistance and cell wall architecture of Candida auris. mSphere 5, e00973-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Geißel, B. et al. Azole-induced cell wall carbohydrate patches kill Aspergillus fumigatus. Nat. Commun. 9, 3098 (2018). This work shows that azole antifungals lead to the formation of carbohydrate patches that penetrate and rupture the cell membrane, leading to cidal effects.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Gow, N. A. R., van de Veerdonk, F. L., Brown, A. J. P. & Netea, M. G. Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat. Rev. Microbiol. 10, 112–122 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Erwig, L. P. & Gow, N. A. R. Interactions of fungal pathogens with phagocytes. Nat. Rev. Microbiol. 14, 163–176 (2016).

    Article  CAS  PubMed  Google Scholar 

  100. Brown, G. D., Willment, J. A. & Whitehead, L. C-Type lectins in immunity and homeostasis. Nat. Rev. Immunol. 18, 374–389 (2018).

    Article  CAS  PubMed  Google Scholar 

  101. Lionakis, M. S., Iliev, I. D. & Hohl, T. M. Immunity against fungi. JCI Insight 2, e93156 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Casadevall, A. Immunity to invasive fungal diseases. Annu. Rev. Immunol. 40, 121–141 (2022).

    Article  PubMed  Google Scholar 

  103. Rappleye, C. A. & Goldman, W. E. Fungal stealth technology. Trends Immunol. 29, 18–24 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Graus, M. S. et al. Mannan molecular substructures control nanoscale glucan exposure in. Candida. Cell Rep. 24, 2432–2442 (2018).

    Article  CAS  PubMed  Google Scholar 

  105. Wheeler, R. T. & Fink, G. R. A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog. 2, e35 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Wheeler, R. T., Kombe, D., Agarwala, S. D. & Fink, G. R. Dynamic, morphotype-specific Candida albicans β-glucan exposure during infection and drug treatment. PLoS Pathog. 4, e1000227 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Cottier, F. et al. Remasking of Candida albicans β-glucan in response to environmental pH is regulated by quorum sensing. mBio 10, e02347-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Pradhan, A. et al. Hypoxia promotes immune evasion by triggering β-glucan masking on the Candida albicans cell surface via mitochondrial and cAMP-protein kinase A signaling. mBio 9, e01318 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Chen, T., Wagner, A. S. & Reynolds, T. B. When is it appropriate to take off the mask? Signaling pathways that regulate β(1,3)-glucan exposure in Candida albicans. Front. Fungal Biol. 3, 842501 (2022).

    Article  Google Scholar 

  110. Lopes, J. P. et al. Evasion of immune surveillance in low oxygen environments enhances Candida albicans virulence. mBio 9, e02120-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Childers, D. S. et al. Epitope shaving promotes fungal immune evasion. mBio 11, e00984-20 (2020). This work shows that the removal of superficial strands of β-1,3-glucan from the Candida cell surface by the β-glucanase Xog1 contributes to the immunological disguise of cells by preventing glucan recognition by the dectin 1 receptor.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Hole, C. R., Lam, W. C., Upadhya, R. & Lodge, J. K. Cryptococcus neoformans chitin synthase 3 plays a critical role in dampening host inflammatory responses. mBio 11, e03373-19 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lam, W. C. et al. Chitosan biosynthesis and virulence in the human fungal pathogen Cryptococcus gattii. mSphere 4, e00644-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Ham, Y. Y., Lewis, J. S. II & Thompson, G. R. III Rezafungin: a novel antifungal for the treatment of invasive candidiasis. Future Microbiol. 16, 27–36 (2021).

    Article  CAS  PubMed  Google Scholar 

  115. Davis, M. R., Donnelley, M. A. & Thompson, G. R. Ibrexafungerp: a novel oral glucan synthase inhibitor. Med. Mycol. 58, 579–592 (2020).

    Article  CAS  PubMed  Google Scholar 

  116. Pfaller, M. A., Huband, M. D., Flamm, R. K., Bien, P. A. & Castanheira, M. Antimicrobial activity of manogepix, a first-in-class antifungal, and comparator agents tested against contemporary invasive fungal isolates from an international surveillance programme (2018–2019). J. Glob. Antimicrob. Resist. 26, 117–127 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Steinbach, W. J. et al. Calcineurin inhibition or mutation enhances cell wall inhibitors against Aspergillus fumigatus. Antimicrob. Agents Chemother. 51, 2979–2981 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Steinbach, W. J., Reedy, J. L., Cramer, R. A. Jr., Perfect, J. R. & Heitman, J. Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections. Nat. Rev. Microbiol. 5, 418–430 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Cavalheiro, M. & Teixeira, M. C. Candida biofilms: threats, challenges, and promising strategies. Front. Med. 5, 28 (2018).

    Article  Google Scholar 

  120. Galdiero, E. et al. Eradication of Candida albicans persister cell biofilm by the membranotropic peptide gH625. Sci. Rep. 10, 5780 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Hussain, K. K. et al. Biosensors and diagnostics for fungal detection. J. Fungi 6, 349 (2020).

    Article  CAS  Google Scholar 

  122. Oliveira, L. V. N., Wang, R., Specht, C. A. & Levitz, S. M. Vaccines for human fungal diseases: close but still a long way to go. NPJ Vaccines 6, 33 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Edwards, J. E. Jr. et al. A fungal immunotherapeutic vaccine (NDV-3A) for treatment of recurrent vulvovaginal candidiasis — a phase 2 randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis. 66, 1928–1936 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Spellberg, B. J. et al. Efficacy of the anti-Candida rAls3p-N or rAls1p-N vaccines against disseminated and mucosal candidiasis. J. Infect. Dis. 194, 256–260 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Datta, K., Lees, A. & Pirofski, L. A. Therapeutic efficacy of a conjugate vaccine containing a peptide mimotope of cryptococcal capsular polysaccharide glucuronoxylomannan. Clin. Vaccin. Immunol. 15, 1176–1187 (2008).

    Article  CAS  Google Scholar 

  126. Devi, S. J. Preclinical efficacy of a glucuronoxylomannan–tetanus toxoid conjugate vaccine of Cryptococcus neoformans in a murine model. Vaccine 14, 841–844 (1996).

    Article  CAS  PubMed  Google Scholar 

  127. Meagher, R. B., Lewis, Z. A., Ambati, S. & Lin, X. Aiming for a bull’s-eye: targeting antifungals to fungi with dectin-decorated liposomes. PLoS Pathog. 17, e1009699 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Rudkin, F. M. et al. Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis. Nat. Commun. 9, 5288 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Palliyil, S. et al. Monoclonal antibodies targeting surface-exposed epitopes of Candida albicans cell wall proteins confer in vivo protection in an infection model. Antimicrob. Agents Chemother. 66, e0195721 (2022).

    Article  PubMed  Google Scholar 

  130. Kalafati, L. et al. Innate immune training of granulopoiesis promotes anti-tumor activity. Cell 183, 771–785.e12 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00857025 (2009).

  132. Walker, L. A., Lenardon, M. D., Preechasuth, K., Munro, C. A. & Gow, N. A. R. Cell wall stress induces alternative fungal cytokinesis and septation strategies. J. Cell Sci. 126, 2668–2677 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. De Nobel, J. G., Klis, F. M., Munnik, T., Priem, J. & Van Den Ende, H. An assay of relative cell wall porosity in Saccharomyces cerevisiae, Kluyveromyces lactis and Schizosaccharomyces pombe. Yeast 6, 483–490 (1990).

    Article  PubMed  Google Scholar 

  134. Bleackley, M. R., Dawson, C. S. & Anderson, M. A. Fungal extracellular vesicles with a focus on proteomic analysis. Proteomics 19, e1800232 (2019).

    Article  PubMed  Google Scholar 

  135. Casadevall, A., Nosanchuk, J. D., Williamson, P. & Rodrigues, M. L. Vesicular transport across the fungal cell wall. Trends Microbiol. 17, 158–162 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Rodrigues, M. L. & Casadevall, A. A two-way road: novel roles for fungal extracellular vesicles. Mol. Microbiol. 110, 11–15 (2018).

    Article  CAS  PubMed  Google Scholar 

  137. Zand Karimi, H. et al. Arabidopsis apoplastic fluid contains sRNA– and circular RNA–protein complexes that are located outside extracellular vesicles. Plant Cell 34, 1863–1881 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

N.A.R.G. acknowledges Wellcome support of Senior Investigator (101873/Z/13/Z) and Collaborative (200208/A/15/Z, 215599/Z/19/Z) Awards, the Medical Research Council (MRC) Centre for Medical Mycology (MR/N006364/2) and the MRC (MR/M026663/2).

Author information

Authors and Affiliations

  1. Medical Research Council Centre for Medical Mycology, School of Biosciences, University of Exeter, Exeter, UK

    Neil A. R. Gow

  2. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia

    Megan D. Lenardon

Authors
  1. Neil A. R. Gow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Megan D. Lenardon
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Neil A. R. Gow or Megan D. Lenardon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Microbiology thanks Jean-Paul Latgé; Peter Lipke; and Tuo Wang, who co-reviewed with Malitha Dickwella Widanage, for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Protoplast

A membrane-bound cell compartment that remains after the cell wall has been removed.

Turgor pressure

The force generated by osmotic expansion of the cell membrane that pushes against the cell wall.

Appressoria

Specialized fungal cells that are used to penetrate plant cells. Very high turgor pressure in the appressoria is used to punch through the host plant cell.

Chitin ghosts

A cell wall preparation in which both the acid and alkali soluble components of the cell wall (proteins, mannans, glucans) are removed, leaving only the insoluble chitin skeleton of the wall.

Osmoticum

A single soluble molecule or a combination of soluble molecules that function to absorb water and create osmotic pressure within a cell.

Conidia

Fungal spores produced by asexual reproduction.

Pattern recognition receptors

(PRRs). Families of immune receptor proteins encoded in the germ line of humans and other animals that recognize molecules that are characteristic of the components of pathogens (pathogen-associated molecular patterns (PAMPs)).

Phages

Viruses that infect microorganisms; for example, bacteriophages are viruses that infect and replicate in bacterial cells.

Extracellular matrix

Extracellular polymers, including polysaccharides, proteins, lipids and nucleic acids, that are secreted by and surround microorganisms within a biofilm.

Exocyst complex

A complex of proteins normally found at sites of active cell growth that function in gathering and tethering secretory vesicles to the cell membrane.

Pathogen-associated molecular patterns

(PAMPs). Components of pathogens, usually cell surface molecules, that are recognized by pattern recognition receptors (PRRs) and trigger immune responses.

Triterpenoid

A class of molecules formed from three terpene units or six isoprene units that serve as precursors to fungal steroids.

Membranotopic peptide

A class of peptides that have a natural affinity and ability to interact with cell membranes.

Persister cells

Subpopulations of cells, usually within a biofilm, that are not resistant to but can survive exposure to an antimicrobial agent by becoming temporarily quiescent. Persister cells can seed regrowth of the microorganisms once the antimicrobial is removed.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gow, N.A.R., Lenardon, M.D. Architecture of the dynamic fungal cell wall. Nat Rev Microbiol 21, 248–259 (2023). https://doi.org/10.1038/s41579-022-00796-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41579-022-00796-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing