Relationship between capsule formation and drug resistance of Cryptococcus

Authors

  • Chuhan Wang

DOI:

https://doi.org/10.54097/f7t5ye62

Keywords:

Cryptococcus, capsule, drug resistance.

Abstract

The polysaccharide capsule of Cryptococcus plays a pivotal role in both its pathogenicity and resistance to antifungal therapies. This capsule acts as a physical barrier, impeding the penetration of antifungal drugs and thereby reducing their efficacy in killing fungal cells. Moreover, chemical modifications of the capsule, including acetylation and xylosylation, further enhance its resistance to drugs, particularly azole antifungals. Beyond its role in drug resistance, the capsule also facilitates immune evasion, enabling Cryptococcus to survive and persist within the host by interfering with the host's immune defenses. Recent studies have highlighted the importance of glucuronoxylomannan (GXM) and its modified sugar derivatives in the structure and function of the capsule. However, the precise mechanisms governing the transport and interactions involved in the assembly of the capsule’s fibrillar network remain poorly understood. Furthermore, alterations in capsule composition, density, and modification significantly influence the pathogen's resistance to antibiotics. Future research is needed to elucidate the synthesis, modification, and assembly processes of the capsule, as well as its specific contributions to drug resistance and immune evasion. Such insights could provide new therapeutic targets and strategies for combating Cryptococcus infections.

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References

[1] Fang W, Fa Z, Liao W. Epidemiology of Cryptococcus and cryptococcosis in China. Fungal Genet Biol. 2015 May; 78:7-15.

[2] Robbins N, Caplan T, Cowen LE. Molecular Evolution of Antifungal Drug Resistance. Annu Rev Microbiol. 2017 Sep 8; 71:753-775.

[3] Bandalizadeh Z, Shokohi T, Badali H, Abastabar M, Babamahmoudi F, Davoodi L, Mardani M, Javanian M, Cheraghmakani H, Sepidgar AA, Badiee P, Khodavaisy S, Afshari SAK, Ahmadikia K, Seyedmousavi S. Molecular epidemiology and antifungal susceptibility profiles of clinical Cryptococcus neoformans/Cryptococcus gattii species complex. J Med Microbiol. 2020 Jan;69 (1):72-81.

[4] Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010 Feb 1;50 (3):291-322.

[5] Wu SY, Kang M, Liu Y, Chen ZX, Xiao YL, He C, Ma Y. Molecular epidemiology and antifungal susceptibilities of Cryptococcus species isolates from HIV and non-HIV patients in Southwest China. Eur J Clin Microbiol Infect Dis. 2021 Feb;40 (2):287-295.

[6] Bongomin F, Oladele RO, Gago S, Moore CB, Richardson MD. A systematic review of fluconazole resistance in clinical isolates of Cryptococcus species. Mycoses. 2018 May;61 (5):290-297.

[7] Tobudic S, Kratzer C, Lassnigg A, Presterl E. Antifungal susceptibility of Candida albicans in biofilms. Mycoses. 2012 May;55 (3):199-204.

[8] Robertson EJ, Wolf JM, Casadevall A. EDTA inhibits biofilm formation, extracellular vesicular secretion, and shedding of the capsular polysaccharide glucuronoxylomannan by Cryptococcus neoformans. Appl Environ Microbiol. 2012 Nov;78 (22):7977-84.

[9] Gast CE, Basso LR Jr, Bruzual I, Wong B. Azole resistance in Cryptococcus gattii from the Pacific Northwest: Investigation of the role of ERG11. Antimicrob Agents Chemother. 2013 Nov;57 (11):5478-85.

[10] Xiang MJ, Liu JY, Ni PH, Wang S, Shi C, Wei B, Ni YX, Ge HL. Erg11 mutations associated with azole resistance in clinical isolates of Candida albicans. FEMS Yeast Res. 2013 Jun;13 (4):386-93.

[11] Bosco-Borgeat ME, Mazza M, Taverna CG, Córdoba S, Murisengo OA, Vivot W, Davel G. Amino acid substitution in Cryptococcus neoformans lanosterol 14-α-demethylase involved in fluconazole resistance in clinical isolates. Rev Argent Microbiol. 2016 Apr-Jun;48 (2):137-42.

[12] Basso LR Jr, Gast CE, Bruzual I, Wong B. Identification and properties of plasma membrane azole efflux pumps from the pathogenic fungi Cryptococcus gattii and Cryptococcus neoformans. J Antimicrob Chemother. 2015 May;70 (5):1396-407.

[13] Chang M, Sionov E, Khanal Lamichhane A, Kwon-Chung KJ, Chang YC. Roles of Three Cryptococcus neoformans and Cryptococcus gattii Efflux Pump-Coding Genes in Response to Drug Treatment. Antimicrob Agents Chemother. 2018 Mar 27;62 (4): e01751-17.

[14] Mondon P, Petter R, Amalfitano G, Luzzati R, Concia E, Polacheck I, Kwon-Chung KJ. Heteroresistance to fluconazole and voriconazole in Cryptococcus neoformans. Antimicrob Agents Chemother. 1999 Aug;43 (8):1856-61.

[15] Chang YC, Khanal Lamichhane A, Kwon-Chung KJ. Cryptococcus neoformans, Unlike Candida albicans, Forms Aneuploid Clones Directly from Uninucleated Cells under Fluconazole Stress. mBio. 2018 Dec 4;9 (6):e01290-18.

[16] Stone NR, Rhodes J, Fisher MC, Mfinanga S, Kivuyo S, Rugemalila J, Segal ES, Needleman L, Molloy SF, Kwon-Chung J, Harrison TS, Hope W, Berman J, Bicanic T. Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis. J Clin Invest. 2019 Mar 1;129 (3):999-1014.

[17] Chang Z, Yadav V, Lee SC, Heitman J. Epigenetic mechanisms of drug resistance in fungi. Fungal Genet Biol. 2019 Nov;132:103253.

[18] Brandão F, Esher SK, Ost KS, Pianalto K, Nichols CB, Fernandes L, Bocca AL, Poças-Fonseca MJ, Alspaugh JA. HDAC genes play distinct and redundant roles in Cryptococcus neoformans virulence. Sci Rep. 2018 Mar 26;8 (1):5209.

[19] Gates MA, Kozel TR. Differential localization of complement component 3 within the capsular matrix of Cryptococcus neoformans. Infect Immun. 2006 Jun;74 (6):3096-106.

[20] McClelland EE, Bernhardt P, Casadevall A. Estimating the relative contributions of virulence factors for pathogenic microbes. Infect Immun. 2006 Mar;74 (3):1500-4.

[21] Martinez LR, Casadevall A. Specific antibody can prevent fungal biofilm formation and this effect correlates with protective efficacy. Infect Immun. 2005 Oct;73 (10):6350-62.

[22] Kozel TR, et al. 2003. Antigenic and biological characteristics of mutant strains of Cryptococcus neoformans lacking capsular O-acetylation or xylosyl side chains. Infect. Immun. 71:2868–2875.

[23] Moyrand F, Chang YC, Himmelreich U, Kwon-Chung KJ, Janbon G. Cas3p belongs to a seven-member family of capsule structure designer proteins. Eukaryot Cell. 2004 Dec;3 (6):1513-24.

[24] McFadden DC, De Jesus M, Casadevall A. The physical properties of the capsular polysaccharides from Cryptococcus neoformans suggest features for capsule construction. J Biol Chem. 2006 Jan 27;281 (4):1868-75.

[25] Heiss C, Klutts JS, Wang Z, Doering TL, Azadi P. 2009. The structure of Cryptococcus neoformans galactoxylomannan contains beta-d-glucuronic acid. Carbohydr. Res. 344:915–920.

[26] Gates MA, Thorkildson P, Kozel TR. 2004. Molecular architecture of the Cryptococcus neoformans capsule. Mol. Microbiol. 52:13–24.

[27] Gates-Hollingsworth MA, Kozel TR. 2009. Phenotypic heterogeneity in expression of epitopes in the Cryptococcus neoformans capsule. Mol. Microbiol. 74:126–138.

[28] Cordero RJB, Frases S, Guimaräes AJ, Rivera J, Casadevall A. 2011. Evidence for branching in cryptococcal capsular polysaccharides and consequences on its biological activity. Mol. Microbiol. 79:1101–1117.

[29] McFadden DC, Fries BC, Wang F, Casadevall A. 2007. Capsule structural heterogeneity and antigenic variation in Cryptococcus neoformans. Eukaryot. Cell 6:1464–1473.

[30] Charlier C, et al. 2005. Capsule structure changes associated with Cryptococcus neoformans crossing of the blood-brain barrier. Am. J. Pathol. 166:421–432.

[31] De Jesus M, Chow S-K, Cordero RJB, Frases S, Casadevall A. 2010. Galactoxylomannans from Cryptococcus neoformans varieties neoformans and grubii are structurally and antigenically variable. Eukaryot. Cell 9:1018–1028

[32] Feldmesser M, Kress Y, Casadevall A. 2001. Dynamic changes in the morphology of Cryptococcus neoformans during murine pulmonary infection. Microbiology 147:2355–2365

[33] Garcia-Rodas R, Casadevall A, Rodriguez-Tudela JL, Cuenca-Estrella M, Zaragoza O. 2011. Cryptococcus neoformans capsular enlargement and cellular gigantism during Galleria mellonella infection. PLoS One 6:e24485

[34] Guimarães AJ, et al. 2010. Cryptococcus neoformans responds to mannitol by increasing capsule size in vitro and in vivo. Cell. Microbiol. 12:740–753

[35] Griffith CL, Klutts JS, Zhang L, Levery SB, Doering TL. 2004. UDP-glucose dehydrogenase plays multiple roles in the biology of the pathogenic fungus Cryptococcus neoformans. J. Biol. Chem. 279:51669–51676

[36] Jacobson ES, Payne WR. 1982. UDP glucuronate decarboxylase and synthesis of capsular polysaccharide in Cryptococcus neoformans. J. Bacteriol. 152:932–934

[37] Moyrand F, Janbon G. 2004. UGD1, encoding the Cryptococcus neoformans UDP-glucose dehydrogenase, is essential for growth at 37 degrees C and for capsule biosynthesis. Eukaryot. Cell 3:1601–1608.

[38] Bar-Peled M, Griffith CL, Doering TL. 2001. Functional cloning and characterization of a UDP-glucuronic acid decarboxylase: the pathogenic fungus Cryptococcus neoformans elucidates UDP-xylose synthesis. Proc. Natl. Acad. Sci. U. S. A. 98:12003-12008.

[39] Moyrand F, Lafontaine I, Fontaine T, Janbon G. 2008. UGE1 and UGE2 regulate the UDP-glucose/UDP-galactose equilibrium in Cryptococcus neoformans. Eukaryot. Cell 7:2069–2077.

[40] Wills EA, et al. 2001. Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity. Mol. Microbiol. 40:610–620.

[41] Castle SA, et al. 2008. Beta 1,2-xylosyltransferase Cxt1p is solely responsible for xylose incorporation into Cryptococcus neoformans glycosphingolipids. Eukaryot. Cell 7:1611–1615

[42] Klutts JS, Doering TL. 2008. Cryptococcal xylosyltransferase 1 (Cxt1p) from Cryptococcus neoformans plays a direct role in the synthesis of capsule polysaccharides. J. Biol. Chem. 283:14327–14334

[43] Klutts JS, Levery SB, Doering TL. 2007. A beta-1,2-xylosyltransferase from Cryptococcus neoformans defines a new family of glycosyltransferases. J. Biol. Chem. 282:17890–17899

[44] Cottrell TR, Griffith CL, Liu H, Nenninger AA, Doering TL. 2007. The pathogenic fungus Cryptococcus neoformans expresses two functional GDP-mannose transporters with distinct expression patterns and roles in capsule synthesis. Eukaryot. Cell 6:776–785

[45] Doering TL. 1999. A unique alpha-1,3 mannosyltransferase of the pathogenic fungus Cryptococcus neoformans. J. Bacteriol. 181:5482–5488

[46] Sommer U, Liu H, Doering TL. 2003. An alpha-1,3-mannosyltransferase of Cryptococcus neoformans. J. Biol. Chem. 278:47724–47730

[47] Janbon G, Himmelreich U, Moyrand F, Improvisi L, Dromer F. 2001. Cas1p is a membrane protein necessary for the O-acetylation of the Cryptococcus neoformans capsular polysaccharide. Mol. Microbiol. 42:453–467

[48] Kozel TR, et al. 2003. Antigenic and biological characteristics of mutant strains of Cryptococcus neoformans lacking capsular O-acetylation or xylosyl side chains. Infect. Immun. 71:2868–2875

[49] Moyrand F, Chang YC, Himmelreich U, Kwon-Chung KJ, Janbon G. 2004. Cas3p belongs to a seven-member family of capsule structure designer proteins. Eukaryot. Cell 3:1513–1524

[50] Jong A, et al. 2007. Identification and characterization of CPS1 as a hyaluronic acid synthase contributing to the pathogenesis of Cryptococcus neoformans infection. Eukaryot. Cell 6:1486–1496

[51] Chang YC, Jong A, Huang S, Zerfas P, Kwon-Chung KJ. 2006. CPS1, a homolog of the Streptococcus pneumoniae type 3 polysaccharide synthase gene, is important for the pathobiology of Cryptococcus neoformans. Infect. Immun. 74:3930–3938.

[52] Jong A, et al. 2008. Invasion of Cryptococcus neoformans into human brain microvascular endothelial cells requires protein kinase C activation. Cell. Microbiol. 10:1854–1865

[53] Jong A, et al. 2007. Identification and characterization of CPS1 as a hyaluronic acid synthase contributing to the pathogenesis of Cryptococcus neoformans infection. Eukaryot. Cell 6:1486–1496。

[54] Geisinger E, Isberg RR. Antibiotic modulation of capsular exopolysaccharide and virulence in Acinetobacter baumannii. PLoS Pathog. 2015 Feb 13;11 (2):e1004691.

[55] Yuan J, Chen C, Cui J, Lu J, Yan C, Wei X, Zhao X, Li N, Li S, Xue G, Cheng W, Li B, Li H, Lin W, Tian C, Zhao J, Han J, An D, Zhang Q, Wei H, Zheng M, Ma X, Li W, Chen X, Zhang Z, Zeng H, Ying S, Wu J, Yang R, Liu D. 2019. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metab 30:675–688.e7.

[56] Paczosa MK, Mecsas J. 2016. Klebsiella pneumoniae: going on the offense with a strong defense. Microbiol Mol Biol Rev 80:629–661. doi: 10.1128/MMBR.00078-15.

[57] Fan Z, Fu T, Liu H, Li Z, Du B, Cui X, Zhang R, Feng Y, Zhao H, Xue G, Cui J, Yan C, Gan L, Feng J, Xu Z, Yu Z, Tian Z, Ding Z, Chen J, Chen Y, Yuan J. Glucose Induces Resistance to Polymyxins in High-Alcohol-Producing Klebsiella pneumoniae via Increasing Capsular Polysaccharide and Maintaining Intracellular ATP. Microbiol Spectr. 2023 Aug 17;11 (4):e0003123.

[58] Brogden K. A. 2005; Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?. Nat Rev Microbiol 3:238–250.

[59] Nicolas P., Mor A. 1995; Peptides as weapons against microorganisms in the chemical defence system of vertebrates. Annu Rev Microbiol 49:277–304.

[60] Nizet V. 2006; Antimicrobial peptide resistance mechanisms of human bacterial pathogens. Curr Issues Mol Biol 8:11–26.

[61] Llobet E, Tomás JM, Bengoechea JA. Capsule polysaccharide is a bacterial decoy for antimicrobial peptides. Microbiology (Reading). 2008 Dec;154(Pt 12):3877-3886.

[62] Sabnis, A., Ledger, E. V. K., Pader, V. & Edwards, A. M. Antibiotic interceptors: Creating safe spaces for bacteria. PLoS Pathog. 14, e1006924 (2018).

[63] Chen, C. H. & Lu, T. K. Development and challenges of antimicrobial peptides for therapeutic applications. Antibiotics 9, 24 (2020).

[64] Gendrin, C. et al. Diminished capsule exacerbates virulence, blood-brain barrier penetration, intracellular persistence, and antibiotic evasion of Hyperhemolytic Group B Streptococci. J. Infect. Dis. 217, 1128–1138 (2018).

[65] Groisman, E. A. Feedback control of two-component regulatory systems. Annu. Rev. Microbiol. 70, 103–124 (2016).

[66] Jacob-Dubuisson, F., Mechaly, A., Betton, J. M. & Antoine, R. Structural insights into the signalling mechanisms of two-component systems. Nat. Rev. Microbiol 16, 585–593 (2018).

[67] Tzeng, Y. L., Thomas, J. & Stephens, D. S. Regulation of capsule in Neisseria meningitidis. Crit. Rev. Microbiol 42, 759–772 (2016).

[68] Gao S, Jin W, Quan Y, Li Y, Shen Y, Yuan S, Yi L, Wang Y, Wang Y. Bacterial capsules: Occurrence, mechanism, and function. NPJ Biofilms Microbiomes. 2024 Mar 13;10 (1):21.

[69] Rajasingham R, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect. Dis. 2017;17:873–881. doi: 10.1016/S1473-3099 (17)30243-8.

[70] Saag MS, et al. Practice guidelines for the management of Cryptococcal disease. Clin. Infect. Dis. 2000;30:710–718. doi: 10.1086/313757.

[71] Bennett JE, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N. Engl. J. Med. 1979;301:126–131. doi: 10.1056/NEJM197907193010303.

[72] Billmyre RB, Applen Clancey S, Li LX, Doering TL, Heitman J. 5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus. Nat Commun. 2020 Jan 8;11 (1):127.

[73] Akoh CC, Lee GC, Liaw YC, Huang TH, Shaw JF. GDSL family of serine esterases/lipases. Prog Lipid Res. 2004 Nov;43 (6):534-52.

[74] Bryan RA, Zaragoza O, Zhang T, Ortiz G, Casadevall A, Dadachova E. Radiological studies reveal radial differences in the architecture of the polysaccharide capsule of Cryptococcus neoformans. Eukaryot Cell. 2005 Feb;4 (2):465-75.

[75] Robbins JB, Austrian R, Lee CJ, Rastogi SC, Schiffman G, Henrichsen J, Mäkelä PH, Broome CV, Facklam RR, Tiesjema RH, et al. Considerations for formulating the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J Infect Dis. 1983 Dec;148 (6):1136-59.

[76] Feldmesser M, Harris C, Reichberg S, Khan S, Casadevall A. 1996. Serum cryptococcal antigen in patients with AIDS. Clin. Infect. Dis. 23:827–830

[77] Haynes BC, et al. 2011. Toward an integrated model of capsule regulation in Cryptococcus neoformans. PLoS Pathog.

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Published

25-12-2024

How to Cite

Wang, C. (2024). Relationship between capsule formation and drug resistance of Cryptococcus. Highlights in Science, Engineering and Technology, 123, 740-751. https://doi.org/10.54097/f7t5ye62