Architecture of the dynamic fungal cell wall | Nature Reviews Microbiology

2022-10-22 12:38:28 By : Ms. Dorothy Meng

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Architecture of the dynamic fungal cell wall | Nature Reviews Microbiology

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.

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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 

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 

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 

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 

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

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.

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 

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 

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

Article  CAS  PubMed  Google Scholar 

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

Article  PubMed  PubMed Central  Google Scholar 

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

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 

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

Article  CAS  PubMed  Google Scholar 

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

Article  CAS  PubMed  Google Scholar 

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 

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

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 

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

Article  CAS  PubMed  Google Scholar 

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

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

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 

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

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 

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 

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 

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 

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

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 

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 

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).

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).

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 

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 

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

Article  CAS  PubMed  Google Scholar 

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 

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).

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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

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

Article  CAS  PubMed  Google Scholar 

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).

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

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 

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 

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 

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 

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 

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).

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 

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 

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 

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

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.

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).

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 

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

Article  CAS  PubMed  Google Scholar 

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

Article  CAS  PubMed  Google Scholar 

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 

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 

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 

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 

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  PubMed Central  Google Scholar 

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 

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 

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 

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 

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 

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 

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 

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).

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

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 

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

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 

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 

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).

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 

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).

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 

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 

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 

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 

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 Central  Google Scholar 

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 

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 

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 

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 

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 

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 

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

Article  PubMed Central  Google Scholar 

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

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

Article  CAS  PubMed  Google Scholar 

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 

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 

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 

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 

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 

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).

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 

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 

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 

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 

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 

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 

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 

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 

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 

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

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 

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

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 

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 

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 

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).

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 

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 

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 

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).

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 

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

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 

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).

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

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 

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 

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 

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).

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

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

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The authors contributed equally to all aspects of the article.

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

The authors declare no competing interests.

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.

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

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

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.

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.

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

Fungal spores produced by asexual reproduction.

(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)).

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

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

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

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

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

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

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.

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.

Gow, N.A.R., Lenardon, M.D. Architecture of the dynamic fungal cell wall. Nat Rev Microbiol (2022). https://doi.org/10.1038/s41579-022-00796-9

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

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Architecture of the dynamic fungal cell wall | Nature Reviews Microbiology

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