Adapting to survive: How Candida overcomes host-imposed constraints during human colonization

1. Kumamoto CA. Inflammation and gastrointestinal Candida colonization. Current Opinion in Microbiology. 2011;14(4): 386–391. doi: 10.1016/j.mib.2011.07.015 21802979

2. Limon JJ, Skalski JH, Underhill DM. Commensal Fungi in Health and Disease. Cell Host Microbe. 2017;22: 156–165. doi: 10.1016/j.chom.2017.07.002 28799901

3. Cauchie M, Desmet S, Lagrou K. Candida and its dual lifestyle as a commensal and a pathogen. Res Microbiol. 2017;168: 802–810. doi: 10.1016/j.resmic.2017.02.005 28263903

4. Pappas PG, Lionakis MS, Arendrup MC, Ostrosky-Zeichner L, Kullberg BJ. Invasive candidiasis. Nat Rev Dis Prim. 2018;4: 18026. doi: 10.1038/nrdp.2018.26 29749387

5. Tsai M-H, Hsu J-F, Yang L-Y, Pan Y-B, Lai M-Y, Chu S-M, et al. Candidemia due to uncommon Candida species in children: new threat and impacts on outcomes. Sci Rep. 2018;8: 15239. doi: 10.1038/s41598-018-33662-x 30323257

6. Singh S, Sobel JD, Bhargava P, Boikov D, Vazquez JA. Vaginitis Due to Candida krusei: Epidemiology, Clinical Aspects, and Therapy. Clin Infect Dis. 2002;35(9): 1066–1070. doi: 10.1086/343826 12384840

7. Bougnoux ME, Brun S, Zahar JR. Healthcare-associated fungal outbreaks: new and uncommon species, new molecular tools for investigation and prevention. Antimicrobial Resistance and Infection Control. 2018;7: 45. doi: 10.1186/s13756-018-0338-9 29599969

8. Kohlenberg A, Struelens MJ, Monnet DL, Plachouras D, Apfalter P, Lass-Flörl C, et al. Candida auris: Epidemiological situation, laboratory capacity and preparedness in European Union and European economic area countries, 2013 to 2017. Eurosurveillance. 2018;23(13): 18–00136. doi: 10.2807/1560-7917.ES.2018.23.13.18-00136

9. Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother. 2005;49(9): 3640–3645. doi: 10.1128/AAC.49.9.3640-3645.2005 16127033

10. Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. The Lancet Infectious Diseases. 2017;17(12): e383–e392. doi: 10.1016/S1473-3099(17)30316-X 28774698

11. Pfaller MA, Diekema DJ, Turnidge JD, Castanheira M, Jones RN. Twenty years of the SENTRY Antifungal Surveillance Program: Results for Candida species from 1997–2016. Open Forum Infect Dis. 2019;6(Suppl. 1): S79–S94. doi: 10.1093/ofid/ofy358 30895218

12. Nobile CJ, Johnson AD. Candida albicans Biofilms and Human Disease. Annu Rev Microbiol. 2015;69: 71–92. doi: 10.1146/annurev-micro-091014-104330 26488273

13. Demers EG, Biermann AR, Masonjones S, Crocker AW, Ashare A, Stajich JE, et al. Evolution of drug resistance in an antifungal-naive chronic Candida lusitaniae infection. Proc Natl Acad Sci U S A. 2018;115(47): 12040–12045. doi: 10.1073/pnas.1807698115 30389707

14. Thompson DS, Carlisle PL, Kadosh D. Coevolution of morphology and virulence in Candida species. Eukaryotic Cell. 2011;10(9): 1173–1182. doi: 10.1128/EC.05085-11 21764907

15. Noble SM, Gianetti BA, Witchley JN. Candida albicans cell-type switching and functional plasticity in the mammalian host. Nature Reviews Microbiology. 2017;15(2): 96–108. doi: 10.1038/nrmicro.2016.157 27867199

16. Tao L, Du H, Guan G, Dai Y, Nobile CJ, Liang W, et al. Discovery of a “White-Gray-Opaque” Tristable Phenotypic Switching System in Candida albicans: Roles of Non-genetic Diversity in Host Adaptation. PLoS Biol. 2014;12(4): e1001830. doi: 10.1371/journal.pbio.1001830 24691005

17. Pande K, Chen C, Noble SM. Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism. Nat Genet. 2013;45(9): 1088–1091. doi: 10.1038/ng.2710 23892606

18. Hopke A, Brown AJP, Hall RA, Wheeler RT. Dynamic Fungal Cell Wall Architecture in Stress Adaptation and Immune Evasion. Trends in Microbiology. 2018;26(4): 284–295. doi: 10.1016/j.tim.2018.01.007 29452950

19. Garcia-Rubio R, de Oliveira HC, Rivera J, Trevijano-Contador N. The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species. Frontiers in Microbiology. 2020;10: 2993. doi: 10.3389/fmicb.2019.02993 31993032

20. Johnston M. Feasting, fasting and fermenting: Glucose sensing in yeast and other cells. Trends in Genetics. 1999;15(1): 29–33. doi: 10.1016/s0168-9525(98)01637-0 10087931

21. Ene IV., Brunke S, Brown AJP, Hube B. Metabolism in fungal pathogenesis. Cold Spring Harb Perspect Med. 2014;4(12): a019695. doi: 10.1101/cshperspect.a019695 25190251

22. Carlson M. Glucose repression in yeast. Curr Opin Microbiol. 1999;2(2): 202–207. doi: 10.1016/S1369-5274(99)80035-6 10322167

23. Yin Z, Smith RJ, Brown AJP. Multiple signalling pathways trigger the exquisite sensitivity of yeast gluconeogenic mRNAs to glucose. Mol Microbiol. 1996;20(4): 751–764. doi: 10.1111/j.1365-2958.1996.tb02514.x 8793872

24. López-Boado YS, Herrero P, Gascón S, Moreno F. Catabolite inactivation of isocitrate lyase from Saccharomyces cerevisiae. Arch Microbiol. 1987;147(3): 231–234. doi: 10.1007/BF00463480 3036035

25. Holzer H. Proteolytic catabolite inactivation in Saccharomyces cerevisiae. Revisiones sobre biologia celular: RBC. 1989;21: 305–319. 2561496

26. Sandai D, Yin Z, Selway L, Stead D, Walker J, Leach MD, et al. The evolutionary rewiring of ubiquitination targets has reprogrammed the regulation of carbon assimilation in the pathogenic yeast Candida albicans. mBio. 2012;3(6): e00495–12. doi: 10.1128/mBio.00495-12 23232717

27. Childers DS, Raziunaite I, Mol Avelar G, Mackie J, Budge S, Stead D, et al. The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence. PLoS Pathog. 2016;12(4): e1005566. doi: 10.1371/journal.ppat.1005566 27073846

28. Barelle CJ, Priest CL, MacCallum DM, Gow NAR, Odds FC, Brown AJP. Niche-specific regulation of central metabolic pathways in a fungal pathogen. Cell Microbiol. 2006;8: 961–971. doi: 10.1111/j.1462-5822.2005.00676.x 16681837

29. Hudson DA, Sciascia QL, Sanders RJ, Norris GE, Edwards PJB, Sullivan PA, et al. Identification of the dialysable serum inducer of germ-tube formation in Candida albicans. Microbiology. 2004;150(Pt 9): 3041–3049. doi: 10.1099/mic.0.27121-0 15347762

30. Buu LM, Chen YC. Impact of glucose levels on expression of hypha-associated secreted aspartyl proteinases in Candida albicans. J Biomed Sci. 2014;21: 22. doi: 10.1186/1423-0127-21-22 24628998

31. Maidan MM, Thevelein JM, Van Dijck P. Carbon source induced yeast-to-hypha transition in Candida albicans is dependent on the presence of amino acids and on the G-protein-coupled receptor Gpr1. Biochemical Society Transactions. 2005;33(Pt 1): 291–293. doi: 10.1042/BST0330291 15667329

32. Mandal SM, Mahata D, Migliolo L, Parekh A, Addy PS, Mandal M, et al. Glucose directly promotes antifungal resistance in the fungal pathogen, Candida spp. J Biol Chem. 2014;289(37): 25468–25473. doi: 10.1074/jbc.C114.571778 25053418

33. Rodaki A, Bohovych IM, Enjalbert B, Young T, Odds FC, Gow NAR, et al. Glucose promotes stress resistance in the fungal pathogen Candida albicans. Mol Biol Cell. 2009;20(22): 4845–4855. doi: 10.1091/mbc.E09-01-0002 19759180

34. Tucey TM, Verma J, Harrison PF, Snelgrove SL, Lo TL, Scherer AK, et al. Glucose Homeostasis Is Important for Immune Cell Viability during Candida Challenge and Host Survival of Systemic Fungal Infection. Cell Metab. 2018;27(5): 988–1006.e7. doi: 10.1016/j.cmet.2018.03.019 29719235

35. Fradin C, Kretschmar M, Nichterlein T, Gaillardin C, D’Enfert C, Hube B. Stage-specific gene expression of Candida albicans in human blood. Mol Microbiol. 2003;47(6): 1523–1543. doi: 10.1046/j.1365-2958.2003.03396.x 12622810

36. Fradin C, De Groot P, MacCallum D, Schaller M, Klis F, Odds FC, et al. Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood. Mol Microbiol. 2005;56(2): 397–415. doi: 10.1111/j.1365-2958.2005.04557.x 15813733

37. Lorenz MC, Fink GR. The glyoxylate cycle is required for fungal virulence. Nature. 2001;412: 83–86. doi: 10.1038/35083594 11452311

38. Naseem S, Min K, Spitzer D, Gardin J, Konopka JB. Regulation of hyphal growth and N-acetylglucosamine catabolism by two transcription factors in Candida albicans. Genetics. 2017;206(1): 299–314. doi: 10.1534/genetics.117.201491 28348062

39. Su C, Lu Y, Liu H. N-acetylglucosamine sensing by a GCN5-related N-acetyltransferase induces transcription via chromatin histone acetylation in fungi. Nat Commun. 2016;7: 12916. doi: 10.1038/ncomms12916 27694804

40. Alvarez FJ, Konopka JB. Identification of an N-acetylglucosamine transporter that mediates hyphal induction in Candida albicans. Mol Biol Cell. 2007;18(3):965–975. Epub 27 Dec 2006. doi: 10.1091/mbc.E06-10-0931 17192409

41. Huang G, Yi S, Sahni N, Daniels KJ, Srikantha T, Soll DR. N-acetylglucosamine induces white to opaque switching, a mating prerequisite in Candida albicans. PLoS Pathog. 2010;6(3): e1000806. doi: 10.1371/journal.ppat.1000806 20300604

42. Simonetti N, Strippoli V, Cassone A. Yeast-mycelial conversion induced by N-acetyl-D-glucosamine in Candida albicans. Nature. 1974;250(464): 344–346. doi: 10.1038/250344a0 4605454

43. Du H, Guan G, Li X, Gulati M, Tao L, Cao C, et al. N-Acetylglucosamine-induced cell death in Candida albicans and its implications for adaptive mechanisms of nutrient sensing in yeasts. MBio. 2015;6(5): e01376–15. doi: 10.1128/mBio.01376-15 26350972

44. Vesely EM, Williams RB, Konopka JB, Lorenz MC. N-Acetylglucosamine Metabolism Promotes Survival of Candida albicans in the Phagosome. mSphere. 2017;2(5): e00357–17. doi: 10.1128/mSphere.00357-17 28904994

45. Butler G, Rasmussen MD, Lin MF, Santos MAS, Sakthikumar S, Munro CA, et al. Evolution of pathogenicity and sexual reproduction in eight Candida genomes. Nature. 2009;459(7247): 657–662. doi: 10.1038/nature08064 19465905

46. Danhof HA, Vylkova S, Vesely EM, Ford AE, Gonzalez-Garay M, Lorenz MC. Robust Extracellular pH Modulation by Candida albicans during Growth in Carboxylic Acids. mBio. 2016;7(6): e01646–16. doi: 10.1128/mBio.01646-16 27935835

47. Rowland I, Gibson G, Heinken A, Scott K, Swann J, Thiele I, et al. Gut microbiota functions: metabolism of nutrients and other food components. European Journal of Nutrition. 2018;57(1): 1–24. Epub 9 Apr 2017. doi: 10.1007/s00394-017-1445-8 28393285

48. Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. 2016;7(3): 189–200. doi: 10.1080/19490976.2015.1134082 26963409

49. Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ. 2018;361: k2179. doi: 10.1136/bmj.k2179 29899036

50. Owen DH, Katz DF. A vaginal fluid simulant. Contraception. 1999;59: 91–95. doi: 10.1016/s0010-7824(99)00010-4 10361623

51. Vieira N, Casal M, Johansson B, MacCallum DM, Brown AJP, Paiva S. Functional specialization and differential regulation of short-chain carboxylic acid transporters in the pathogen Candida albicans. Mol Microbiol. 2010;75: 1337–1354. doi: 10.1111/j.1365-2958.2009.07003.x 19968788

52. Danhof HA, Lorenz MC. The Candida albicans ATO Gene Family Promotes Neutralization of the Macrophage Phagolysosome. Infect Immun. 2015;83(11): 4416–4426. doi: 10.1128/IAI.00984-15 26351284

53. Soares-Silva I, Paiva S, Kötter P, Entian K-D, Casal M. The disruption of JEN1 from Candida albicans impairs the transport of lactate. Mol Membr Biol. 2004;21: 403–411. doi: 10.1080/09687860400011373 15764370

54. Mota S, Alves R, Carneiro C, Silva S, Brown AJ, Istel F, et al. Candida glabrata susceptibility to antifungals and phagocytosis is modulated by acetate. Front Microbiol. 2015;6: 919. doi: 10.3389/fmicb.2015.00919 26388859

55. Alves R, Mota S, Silva S, Rodrigues C F., Alistair AJ, Henriques M, et al. The carboxylic acid transporters Jen1 and Jen2 affect the architecture and fluconazole susceptibility of Candida albicans biofilm in the presence of lactate. Biofouling. 2017;33: 943–954. doi: 10.1080/08927014.2017.1392514 29094611

56. Alves R, Kastora SL, Gomes-Gonçalves A, Azevedo N, Rodrigues CF, Silva S, et al. Transcriptional responses of Candida glabrata biofilm cells to fluconazole are modulated by the carbon source. NPJ Biofilms Microbiomes. 2020;6: 4. doi: 10.1038/s41522-020-0114-5 31993211

57. Ballou ER, Avelar GM, Childers DS, Mackie J, Bain JM, Wagener J, et al. Lactate signalling regulates fungal β-glucan masking and immune evasion. Nat Microbiol. 2016;2: 16238. doi: 10.1038/nmicrobiol.2016.238 27941860

58. Ene I V., Adya AK, Wehmeier S, Brand AC, Maccallum DM, Gow NAR, et al. Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen. Cell Microbiol. 2012;14: 1319–1335. doi: 10.1111/j.1462-5822.2012.01813.x 22587014

59. Ene I V., Heilmann CJ, Sorgo AG, Walker LA, De Koster CG, Munro CA, 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. 2012;12: 3164–3179. doi: 10.1002/pmic.201200228 22997008

60. Zakikhany K, Naglik JR, Schmidt-westhausen A, Holland G, Schaller M, Hube B. In vivo transcript profiling of Candida albicans identifies a gene essential for interepithelial dissemination. Cell Microbiol. 2007;9(12): 2938–2954. doi: 10.1111/j.1462-5822.2007.01009.x 17645752

61. Lorenz MC, Bender JA, Fink GR. Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell. 2004;3: 1076–1087. doi: 10.1128/EC.3.5.1076-1087.2004 15470236

62. Rubin-Bejerano I, Fraser I, Grisafi P, Fink GR. Phagocytosis by neutrophils induces an amino acid deprivation response in Saccharomyces cerevisiae and Candida albicans. Proc Natl Acad Sci U S A. 2003. doi: 10.1073/pnas.1834481100 12958213

63. Jacobsen ID, Brunke S, Seider K, Schwarzmüller T, Firon A, D’Enfért C, et al. Candida glabrata persistence in mice does not depend on host immunosuppression and is unaffected by fungal amino acid auxotrophy. Infect Immun. 2010;78(3): 1066–1077. doi: 10.1128/IAI.01244-09 20008535

64. Kirsch DR, Whitney RR. Pathogenicity of Candida albicans auxotrophic mutants in experimental infections. Infect Immun. 1991;59(9): 3297–3300. 1879944

65. Alonso-Monge R, Navarro-García F, Molero G, Diez-Orejas R, Gustin M, Pla J, et al. Role of the mitogen-activated protein kinase hog1p in morphogenesis and virulence of Candida albicans. J Bacteriol. 1999;181(10): 3058–3068. 10322006

66. Gropp K, Schild L, Schindler S, Hube B, Zipfel PF, Skerka C. The yeast Candida albicans evades human complement attack by secretion of aspartic proteases. Mol Immunol. 2009;47(2–3): 465–475. doi: 10.1016/j.molimm.2009.08.019 19880183

67. Martínez P, Ljungdahl PO. An ER packaging chaperone determines the amino acid uptake capacity and virulence of Candida albicans. Mol Microbiol. 2004;51(2): 371–384. doi: 10.1046/j.1365-2958.2003.03845.x 14756779

68. Martinez P, Ljungdahl PO. Divergence of Stp1 and Stp2 Transcription Factors in Candida albicans Places Virulence Factors Required for Proper Nutrient Acquisition under Amino Acid Control. Mol Cell Biol. 2005;25(21): 9435–9446. doi: 10.1128/MCB.25.21.9435-9446.2005 16227594

69. Vylkova S, Lorenz MC. Modulation of Phagosomal pH by Candida albicans Promotes Hyphal Morphogenesis and Requires Stp2p, a Regulator of Amino Acid Transport. PLoS Pathog. 2014;10(3): e1003995. doi: 10.1371/journal.ppat.1003995 24626429

70. Vylkova S, Carman AJ, Danhof HA, Collette JR, Zhou H, Lorenz MC. The fungal pathogen Candida albicans autoinduces hyphal morphogenesis by raising extracellular pH. mBio. 2011;2(3): e00055–11. doi: 10.1128/mBio.00055-11 21586647

71. Westman J, Moran G, Mogavero S, Hube B, Grinstein S. Candida albicans hyphal expansion causes phagosomal membrane damage and luminal alkalinization. mBio. 2018;9(5): e01226–18. doi: 10.1128/mBio.01226-18 30206168

72. May RC, Casadevall A. In Fungal Intracellular Pathogenesis, Form Determines Fate. mBio. 2018;9(5): e02092–18. doi: 10.1128/mBio.02092-18 30352939

73. Schrevens S, Van Zeebroeck G, Riedelberger M, Tournu H, Kuchler K, Van Dijck P. Methionine is required for cAMP-PKA-mediated morphogenesis and virulence of Candida albicans. Mol Microbiol;108(3): 258–275. 2018. doi: 10.1111/mmi.13933 29453849

74. Miwa T, Takagi Y, Shinozaki M, Yun CW, Schell WA, Perfect JR, et al. Gpr1, a putative G-protein-coupled receptor, regulates morphogenesis and hypha formation in the pathogenic fungus Candida albicans. Eukaryot Cell. 2004;3(4): 919–931. doi: 10.1128/EC.3.4.919-931.2004 15302825

75. Cornet M, Gaillardin C. pH signaling in human fungal pathogens: A new target for antifungal strategies. Eukaryotic Cell. 2014;13(3): 342–352. doi: 10.1128/EC.00313-13 24442891

76. Ramon AM, Porta A, Fonzi WA. Effect of environmental pH on morphological development of Candida albicans is mediated via the PacC-related transcription factor encoded by PRR2. J Bacteriol. 1999;181(24): 7524–7530. 10601210

77. Porta A, Ramon AM, Fonzi WA. PRR1, a homolog of Aspergillus nidulans palF, controls pH-dependent gene expression and filamentation in Candida albicans. J Bacteriol. 1999;181(24): 7516–7523. 10601209

78. Davis D, Wilson RB, Mitchell AP. RIM101-Dependent and -Independent Pathways Govern pH Responses in Candida albicans. Mol Cell Biol. 2000;20(3): 971–978. doi: 10.1128/mcb.20.3.971-978.2000 10629054

79. Bensen ES, Martin SJ, Li M, Berman J, Davis DA. Transcriptional profiling in Candida albicans reveals new adaptive responses to extracellular pH and functions for Rim101p. Mol Microbiol. 2004;54(5): 1335–1351. doi: 10.1111/j.1365-2958.2004.04350.x 15554973

80. Nobile CJ, Solis N, Myers CL, Fay AJ, Deneault JS, Nantel A, et al. Candida albicans transcription factor Rim101 mediates pathogenic interactions through cell wall functions. Cell Microbiol. 2008;10(11): 2180–2196. doi: 10.1111/j.1462-5822.2008.01198.x 18627379

81. Baek YU, Li M, Davis DA. Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors. Eukaryot Cell. 2008;7(7): 1168–1179. doi: 10.1128/EC.00108-08 18503007

82. Almeida RS, Brunke S, Albrecht A, Thewes S, Laue M, Edwards JE, et al. The hyphal-associated adhesin and invasin Als3 of Candida albicans mediates iron acquisition from host ferritin. PLoS Pathog. 2008;4(11): e1000217. doi: 10.1371/journal.ppat.1000217 19023418

83. Garnaud C, García-Oliver E, Wang Y, Maubon D, Bailly S, Despinasse Q, et al. The rim pathway mediates antifungal tolerance in Candida albicans through newly identified Rim 101 transcriptional targets, including Hsp90 and Ipt1. Antimicrob Agents Chemother. 2018;62(3): e01785–17. doi: 10.1128/AAC.01785-17 29311085

84. Marr KA, Rustad TR, John H R, White TC. The trailing end point phenotype in antifungal susceptibility testing is pH dependent. Antimicrob Agents Chemother. 1999;43(6):1383–1386. doi: 10.1128/aac.43.6.1383 10348757

85. Sherrington SL, Sorsby E, Mahtey N, Kumwenda P, Lenardon MD, Brown I, et al. Adaptation of Candida albicans to environmental pH induces cell wall remodelling and enhances innate immune recognition. PLoS Pathog. 2017;13(5): e1006403. doi: 10.1371/journal.ppat.1006403 28542528

86. Cottier F, Sherrington S, Cockerill S, del Olmo Toledo V, Kissane S, Tournu H, et al. Remasking of Candida albicans β-Glucan in Response to Environmental pH Is Regulated by Quorum Sensing. Alspaugh JA, editor. mBio. 2019;10: e02347–19. doi: 10.1128/mBio.02347-19 31615961

87. Taylor CT. Hypoxia in the Gut. Cell Mol. Gasteroenterol. Hepatol. 2018;5(1): 61–62. doi: 10.1016/j.jcmgh.2017.09.005 29276750

88. Lopes JP, Stylianou M, Backman E, Holmberg S, Jass J, Claesson R, et al. Evasion of Immune Surveillance in Low Oxygen Environments Enhances Candida albicans Virulence. mBio. 2018;9(6): e02120–18. doi: 10.1128/mBio.02120-18 30401781

89. Askew C, Sellam A, Epp E, Hogues H, Mullick A, Nantel A, et al. Transcriptional regulation of carbohydrate metabolism in the human pathogen Candida albicans. PLoS Pathog. 2009;5(10): e1000612. doi: 10.1371/journal.ppat.1000612 19816560

90. Bonhomme J, Chauvel M, Goyard S, Roux P, Rossignol T, D’Enfert C. Contribution of the glycolytic flux and hypoxia adaptation to efficient biofilm formation by Candida albicans. Mol Microbiol. 2011;80(4): 995–1013. doi: 10.1111/j.1365-2958.2011.07626.x 21414038

91. Sellam A, van het Hoog M, Tebbji F, Beaurepaire C, Whiteway M, Nantelc A. Modeling the transcriptional regulatory network that controls the early hypoxic response in Candida albicans. Eukaryot Cell. 2014;13(5): 675–690. doi: 10.1128/EC.00292-13 24681685

92. Setiadi ER, Doedt T, Cottier F, Noffz C, Ernst JF. Transcriptional Response of Candida albicans to Hypoxia: Linkage of Oxygen Sensing and Efg1p-regulatory Networks. J Mol Biol. 2006;361(3): 399–411. doi: 10.1016/j.jmb.2006.06.040 16854431

93. Stichternoth C, Ernst JF. Hypoxic adaptation by Efg1 regulates biofilm formation by Candida albicans. Appl Environ Microbiol. 2009;75(11): 3663–3672. doi: 10.1128/AEM.00098-09 19346360

94. Synnott JM, Guida A, Mulhern-Haughey S, Higgins DG, Butler G. Regulation of the Hypoxic Response in Candida albicans. Eukaryot Cell. 2010;9(11): 1734–1746. doi: 10.1128/EC.00159-10 20870877

95. MacPherson S, Akache B, Weber S, De Deken X, Raymond M, Turcotte B. Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes. Antimicrob Agents Chemother. 2005;49(5): 1745–1752. doi: 10.1128/AAC.49.5.1745-1752.2005 15855491

96. Znaidi S, Weber S, Al-Abdin OZ, Bomme P, Saidane S, Drouin S, et al. Genomewide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance. Eukaryot Cell. 2008;7(5): 836–847. doi: 10.1128/EC.00070-08 18390649

97. Pradhan A, Avelar GM, Bain JM, Childers DS, Larcombe DE, Netea MG, 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. 2018;9(6): e01318–18. doi: 10.1128/mBio.01318-18 30401773

98. Hamanaka RB, Chandel NS. Mitochondrial reactive oxygen species regulate hypoxic signaling. Current Opinion in Cell Biology. 2009;21(6): 894–899. doi: 10.1016/j.ceb.2009.08.005 19781926

99. Waypa GB, Smith KA, Schumacker PT. O2 sensing, mitochondria and ROS signaling: The fog is lifting. Molecular Aspects of Medicine. 2016;47–48: 76–89. doi: 10.1016/j.mam.2016.01.002 26776678

100. Vasicek EM, Berkow EL, Flowers SA, Barker KS, Rogers PD. UPC2 is Universally Essential for Azole Antifungal Resistance in Candida albicans. Eukaryot Cell. 2014;13(7):933–946. doi: 10.1128/EC.00221-13 24659578

101. Kontoyiannis DP, Vaziri I, Hanna HA, Boktour M, Thornby J, Hachem R, et al. Risk Factors for Candida tropicalis Fungemia in Patients with Cancer. Clin Infect Dis. 2001;33(10): 1676–1681. doi: 10.1086/323812 11568858

102. Robert VA, Casadevall A. Vertebrate Endothermy Restricts Most Fungi as Potential Pathogens. J Infect Dis. 2009;200(10): 1623–1626. doi: 10.1086/644642 19827944

103. Casadevall A. Thermal Restriction as an Antimicrobial Function of Fever. PLoS Pathogens. 2016;12(5): e1005577. doi: 10.1371/journal.ppat.1005577 27149668

104. Shapiro RS, Robbins N, Cowen LE. Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease. Microbiol Mol Biol Rev. 2011;75(2): 213–267. doi: 10.1128/MMBR.00045-10 21646428

105. Lindquist S. Heat-shock proteins and stress tolerance in microorganisms. Curr Opin Genet Dev. 1992;2(5): 748–755. doi: 10.1016/s0959-437x(05)80135-2 1458023

106. Nicholls S, Leach MD, Priest CL, Brown AJP. Role of the heat shock transcription factor, Hsf1, in a major fungal pathogen that is obligately associated with warm-blooded animals. Mol Microbiol. 2009;74(4): 844–861. doi: 10.1111/j.1365-2958.2009.06883.x 19818013

107. Leach MD, Tyc KM, Brown AJP, Klipp E. Modelling the regulation of thermal adaptation in Candida albicans, a major fungal pathogen of humans. PLoS ONE. 2012;7(3): e32467. doi: 10.1371/journal.pone.0032467 22448221

108. Duina AA, Kalton HM, Gaber RF. Requirement for Hsp90 and a CyP-40-type cyclophilin in negative regulation of the heat shock response. J Biol Chem. 1998;273(30): 18974–18978. doi: 10.1074/jbc.273.30.18974 9668076

109. Zou J, Guo Y, Guettouche T, Smith DF, Voellmy R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell. 1998;94(4): 471–480. doi: 10.1016/s0092-8674(00)81588-3 9727490

110. Leach MD, Budge S, Walker L, Munro C, Cowen LE, Brown AJP. Hsp90 Orchestrates Transcriptional Regulation by Hsf1 and Cell Wall Remodelling by MAPK Signalling during Thermal Adaptation in a Pathogenic Yeast. PLoS Pathog. 2012;8(12): e1003069. doi: 10.1371/journal.ppat.1003069 23300438

111. Ene I V., Walker LA, Schiavone M, Lee KK, Martin-Yken H, Dague E, et al. Cell wall remodeling enzymes modulate fungal cell wall elasticity and osmotic stress resistance. mBio. 2015;6(4): e00986. doi: 10.1128/mBio.00986-15 26220968

112. Mayer FL, Wilson D, Jacobsen ID, Miramón P, Slesiona S, Bohovych IM, et al. Small but crucial: The novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans. PLoS ONE. 2012;7(6); e38584. doi: 10.1371/journal.pone.0038584 22685587

113. Fu MS, de Sordi L, Mühlschlegel FA. Functional characterization of the small heat shock protein Hsp12p from Candida albicans. PLoS ONE. 2012;7(8); e42894. doi: 10.1371/journal.pone.0042894 22880130

114. Gong Y, Li T, Yu C, Sun S. Candida albicans Heat Shock Proteins and Hsps-Associated Signaling Pathways as Potential Antifungal Targets. Front Cell Infect Microbiol. 2017;7: 520. doi: 10.3389/fcimb.2017.00520 29312897

115. Leach MD, Farrer RA, Tan K, Miao Z, Walker LA, Cuomo CA, et al. Hsf1 and Hsp90 orchestrate temperature-dependent global transcriptional remodelling and chromatin architecture in Candida albicans. Nat Commun. 2016;7: 11704. doi: 10.1038/ncomms11704 27226156

116. Nicholls S, MacCallum DM, Kaffarnik FAR, Selway L, Peck SC, Brown AJP. Activation of the heat shock transcription factor Hsf1 is essential for the full virulence of the fungal pathogen Candida albicans. Fungal Genet Biol. 2011;48(3): 297–305. Epub 9 Sep 2010. doi: 10.1016/j.fgb.2010.08.010 20817114

117. Mason KL, Downward JRE, Falkowski NR, Young VB, Kao JY, Huffnagle GB. Interplay between the gastric bacterial microbiota and Candida albicans during postantibiotic recolonization and gastritis. Infect Immun. 2012;80(1): 150–158. Epub 10 Oct 2011. doi: 10.1128/IAI.05162-11 21986629

118. Mason KL, Downward JRE, Mason KD, Falkowski NR, Eaton KA, Kao JY, et al. Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect Immun. 2012;80(10): 3371–3380. doi: 10.1128/IAI.00449-12 22778094

119. Polke M, Jacobsen ID. Quorum sensing by farnesol revisited. Current Genetics. 2017;63(5): 791–797. doi: 10.1007/s00294-017-0683-x 28247023

120. Hornby JM, Jensen EC, Lisec AD, Tasto JJ, Jahnke B, Shoemaker R, et al. Quorum Sensing in the Dimorphic Fungus Candida albicans Is Mediated by Farnesol. Appl Environ Microbiol. 2001;67(7): 2982–2992. doi: 10.1128/AEM.67.7.2982-2992.2001 11425711

121. Jang SJ, Lee K, Kwon B, You HJ, Ko GP. Vaginal lactobacilli inhibit growth and hyphae formation of Candida albicans. Sci Rep. 2019;9(1): 8121. doi: 10.1038/s41598-019-44579-4 31148560

122. Itapary dos Santos C, Ramos França Y, Duarte Lima Campos C, Quaresma Bomfim MR, Oliveira Melo B, Assunção Holanda R, et al. Antifungal and Antivirulence Activity of Vaginal Lactobacillus Spp. Products against Candida Vaginal Isolates. Pathogens. 2019;8(3): E150. doi: 10.3390/pathogens8030150 31547398

123. Graf K, Last A, Gratz R, Allert S, Linde S, Westermann M, et al. Keeping Candida commensal: How lactobacilli antagonize pathogenicity of Candida albicans in an in vitro gut model. DMM Dis Model Mech. 2019;12(9): dmm039719. doi: 10.1242/dmm.039719 31413153

124. Fan D, Coughlin LA, Neubauer MM, Kim J, Kim MS, Zhan X, et al. Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization. Nature Medicine. 2015;21(7): 808–814. doi: 10.1038/nm.3871 26053625

125. Gaddy JA, Tomaras AP, Actis LA. The Acinetobacter baumannii 19606 OmpA protein plays a role in biofilm formation on abiotic surfaces and in the interaction of this pathogen with eukaryotic cells. Infect Immun. 2009;77(8): 3150–3160. doi: 10.1128/IAI.00096-09 19470746

126. Nash EE, Peters BM, Fidel PL, Noverr MC. Morphology-independent virulence of Candida species during polymicrobial intra-abdominal infections with Staphylococcus aureus. Infect Immun. 2015;84(1): 90–98. doi: 10.1128/IAI.01059-15 26483410

127. Todd OA, Fidel PL, Harro JM, Hilliard JJ, Tkaczyk C, Sellman BR, et al. Candida albicans augments Staphylococcus aureus virulence by engaging the staphylococcal agr quorum sensing system. mBio. 2019;10(3): e00910–19. doi: 10.1128/mBio.00910-19 31164467

128. Schlecht LM, Peters BM, Krom BP, Freiberg JA, Hänsch GM, Filler SG, et al. Systemic Staphylococcus aureus infection mediated by Candida albicans hyphal invasion of mucosal tissue. Microbiol (United Kingdom). 2015;161(Pt 1): 168–181. doi: 10.1099/mic.0.083485-0

129. Childers DS, Avelar GM, Bain JM, Larcombe DE, Pradhan A, Budge S, et al. Impact of the Environment upon the Candida albicans Cell Wall and Resultant Effects upon Immune Surveillance. Curr Top Microbiol Immunol Springer, Berlin, Heidelb. 2019. Forthcoming 2020. https://doi.org/10.1007/82_2019_182

130. Speth C, Rambach G, Würzner R, Lass-Flörl C. Complement and fungal pathogens: An update. Mycoses. 2008;51(6): 477–496. doi: 10.1111/j.1439-0507.2008.01597.x 18705662

131. Filler SG, Sheppard DC. Fungal invasion of normally non-phagocytic host cells. PLoS Pathog. 2006;2(12): e129. doi: 10.1371/journal.ppat.0020129 17196036

132. Kaloriti D, Jacobsen M, Yin Z, Patterson M, Tillmann A, Smith DA, et al. Mechanisms underlying the exquisite sensitivity of Candida albicans to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes. mBio. 2014;5(4): e01334–14. doi: 10.1128/mBio.01334-14 25028425

133. Seider K, Brunke S, Schild L, Jablonowski N, Wilson D, Majer O, et al. The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation. J Immunol. 2011;187(6): 3072–3086. doi: 10.4049/jimmunol.1003730 21849684

134. Brothers KM, Gratacap RL, Barker SE, Newman ZR, Norum A, Wheeler RT. NADPH Oxidase-Driven Phagocyte Recruitment Controls Candida albicans Filamentous Growth and Prevents Mortality. PLoS Pathog. 2013;9(10): e1003634. doi: 10.1371/journal.ppat.1003634 24098114

135. Prolo C, Álvarez MN, Radi R. Peroxynitrite, a potent macrophage-derived oxidizing cytotoxin to combat invading pathogens. BioFactors. 2014;40(2): 215–225. Epub 26 Nov 2013. doi: 10.1002/biof.1150 24281946

136. Enjalbert B, Smith DA, Cornell MJ, Alam I, Nicholls S, Brown AJP, et al. Role of the Hog1 stress-activated protein kinase in the global transcriptional response to stress in the fungal pathogen Candida albicans. Mol Biol Cell. 2006;17(2): 1018–1032. Epub 7 Dec 2005. doi: 10.1091/mbc.E05-06-0501 16339080

137. Enjalbert B, MacCallum DM, Odds FC, Brown AJP. Niche-specific activation of the oxidative stress response by the pathogenic fungus Candida albicans. Infect Immun. 2007;75(5): 2143–2151. doi: 10.1128/IAI.01680-06 17339352

138. Pradhan A, Herrero-de-Dios C, Belmonte R, Budge S, Lopez Garcia A, Kolmogorova A, et al. Elevated catalase expression in a fungal pathogen is a double-edged sword of iron. PLoS Pathog. 2017;13(5): e1006405. doi: 10.1371/journal.ppat.1006405 28542620

139. Smith DA, Nicholls S, Morgan BA, Brown AJP, Quinn J. A conserved stress-activated protein kinase regulates a core stress response in the human pathogen Candida albicans. Mol Biol Cell. 2004;15(9): 4179–4190. doi: 10.1091/mbc.E04-03-0181 15229284

140. Alarco AM, Raymond M. The bZip transcription factor Cap1p is involved in multidrug resistance and oxidative stress response in Candida albicans. J Bacteriol. 1999;181(3): 700–708. 9922230

141. Znaidi S, Barker KS, Weber S, Alarco AM, Liu TT, Boucher G, et al. Identification of the Candida albicans Cap1p regulon. Eukaryot Cell. 2009;8(6): 806–820. doi: 10.1128/EC.00002-09 19395663

142. Zhang X, De Micheli M, Coleman ST, Sanglard D, Moye-Rowley WS. Analysis of the oxidative stress regulation of the Candida albicans transcription factor, Cap1p. Mol Microbiol. 2000;36(3):618–629. doi: 10.1046/j.1365-2958.2000.01877.x 10844651

143. da Silva Dantas A, Patterson MJ, Smith DA, MacCallum DM, Erwig LP, Morgan BA, et al. Thioredoxin Regulates Multiple Hydrogen Peroxide-Induced Signaling Pathways in Candida albicans. Mol Cell Biol. 2010;30(19): 4550–4563. doi: 10.1128/MCB.00313-10 20679492

144. Chiranand W, McLeod I, Zhou H, Lynn JJ, Vega LA, Myers H, et al. CTA4 transcription factor mediates induction of nitrosative stress response in Candida albicans. Eukaryot Cell. 2008;7(2): 268–278. Epub 14 Dec 2007. doi: 10.1128/EC.00240-07 18083829

145. Chaves GM, Bates S, MacCallum DM, Odds FC. Candida albicans GRX2, encoding a putative glutaredoxin, is required for virulence in a murine model. Genetics and Molecular Research. 2007;6(4): 1051–1063. 18273798

146. Hwang CS, Rhie GE, Oh JH, Huh WK, Yim HS, Kang SO. Copper- and zinc-containing superoxide dismutase (Cu/ZnSOD) is required for the protection of Candida albicans against oxidative stresses and the expression of its full virulence. Microbiology. 2002;148(Pt 11): 3705–3713. doi: 10.1099/00221287-148-11-3705 12427960

147. Kos I, Patterson MJ, Znaidi S, Kaloriti D, da Silva Dantas A, Herrero-de-Dios CM, et al. Mechanisms underlying the delayed activation of the cap1 transcription factor in Candida albicans following combinatorial oxidative and cationic stress important for phagocytic potency. mBio. 2016;7(2): e00331. doi: 10.1128/mBio.00331-16 27025253

148. Hood MI, Skaar EP. Nutritional immunity: Transition metals at the pathogen-host interface. Nature Reviews Microbiology. 2012;10(8): 525–537. doi: 10.1038/nrmicro2836 22796883

149. Ramanan N, Wang Y. A high-affinity iron permease essential for Candida albicans virulence. Science. 2000;288(5468): 1062–1064. doi: 10.1126/science.288.5468.1062 10807578

150. Potrykus J, Stead D, MacCallum DM, Urgast DS, Raab A, van Rooijen N, et al. Fungal Iron Availability during Deep Seated Candidiasis Is Defined by a Complex Interplay Involving Systemic and Local Events. PLoS Pathog. 2013;9(10): e1003676. doi: 10.1371/journal.ppat.1003676 24146619

151. Potrykus J, Ballou ER, Childers DS, Brown AJP. Conflicting Interests in the Pathogen-Host Tug of War: Fungal Micronutrient Scavenging Versus Mammalian Nutritional Immunity. PLoS Pathog. 2014;10(3): e1003910. doi: 10.1371/journal.ppat.1003910 24626223

152. Nevitt T, Thiele DJ. Host iron withholding demands siderophore utilization for Candida glabrata to survive macrophage killing. PLoS Pathog. 2011;7(3): e1001322. doi: 10.1371/journal.ppat.1001322 21445236

153. Seider K, Gerwien F, Kasper L, Allert S, Brunke S, Jablonowski N, et al. Immune evasion, stress resistance, and efficient nutrient acquisition are crucial for intracellular survival of Candida glabrata within macrophages. Eukaryot Cell. 2014;13(1): 170–183. Epub 20 Dec 2013. doi: 10.1128/EC.00262-13 24363366

154. Knight SAB, Lesuisse E, Stearman R, Klausner RD, Dancis A. Reductive iron uptake by Candida albicans: Role of copper, iron and the TUP1 regulator. Microbiology. 2002;148(Pt 1): 29–40. doi: 10.1099/00221287-148-1-29 11782496

155. Knight SAB, Vilaire G, Lesuisse E, Dancis A. Iron acquisition from transferrin by Candida albicans depends on the reductive pathway. Infect Immun. 2005;73(9): 5482–5492. doi: 10.1128/IAI.73.9.5482-5492.2005 16113264

156. Kuznets G, Vigonsky E, Weissman Z, Lalli D, Gildor T, Kauffman SJ, et al. A Relay Network of Extracellular Heme-Binding Proteins Drives C. albicans Iron Acquisition from Hemoglobin. PLoS Pathog. 2014;10(10): e1004407. doi: 10.1371/journal.ppat.1004407 25275454

157. Mackie J, Szabo EK, Urgast DS, Ballou ER, Childers DS, MacCallum DM, et al. Host-imposed copper poisoning impacts fungal micronutrient acquisition during systemic Candida albicans infections. PLoS ONE. 2016;11(6): e0158683. doi: 10.1371/journal.pone.0158683 27362522

158. Ballou ER, Wilson D. The roles of zinc and copper sensing in fungal pathogenesis. Current Opinion in Microbiology. 2016;32: 128–134. doi: 10.1016/j.mib.2016.05.013 27327380

159. Li CX, Gleason JE, Zhang SX, Bruno VM, Cormack BP, Culotta VC. Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase. Proc Natl Acad Sci. 2015;112(38): E5336–E5342. doi: 10.1073/pnas.1513447112 26351691

160. Edgeworth J, Gorman M, Bennett R, Freemont P, Hogg N. Identification of p8,14 as a highly abundant heterodimeric calcium binding protein complex of myeloid cells. J Biol Chem. 1991;266(12): 7706–7713. 2019594

161. Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5(10): e1000639. doi: 10.1371/journal.ppat.1000639 19876394

162. Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans and hyphal forms. Cell Microbiol. 2006;8(4): 668–676. doi: 10.1111/j.1462-5822.2005.00659.x 16548892

163. Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, Brown GD, et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol. 2014;15(11): 1017–1025. doi: 10.1038/ni.2987 25217981

164. Miramón P, Kasper L, Hube B. Thriving within the host: Candida spp. interactions with phagocytic cells. Medical Microbiology and Immunology. 2013;202(3): 183–195. doi: 10.1007/s00430-013-0288-z 23354731

165. Vignesh KS, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS. Zinc Sequestration: Arming Phagocyte Defense against Fungal Attack. PLoS Pathog. 2013;9(12): e1003815. doi: 10.1371/journal.ppat.1003815 24385902

166. Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS. Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival. Immunity. 2013;39(4): 697–710. doi: 10.1016/j.immuni.2013.09.006 24138881

167. Kim MJ, Kil M, Jung JH, Kim J. Roles of zinc-responsive transcription factor Csr1 in filamentous growth of the pathogenic yeast Candida albicans. J Microbiol Biotechnol. 2008;18(2): 242–247. 18309267

168. Nobile CJ, Nett JE, Hernday AD, Homann OR, Deneault JS, Nantel A, et al. Biofilm matrix regulation by Candida albicans Zap1. PLoS Biol. 2009;7(6): e1000133. doi: 10.1371/journal.pbio.1000133 19529758

169. Xu W, Solis N V., Ehrlich RL, Woolford CA, Filler SG, Mitchell AP. Activation and Alliance of Regulatory Pathways in C. albicans during Mammalian Infection. PLoS Biol. 2015;13(2): e1002076. doi: 10.1371/journal.pbio.1002076 25693184

170. Citiulo F, Jacobsen ID, Miramón P, Schild L, Brunke S, Zipfel P, et al. Candida albicans scavenges host zinc via Pra1 during endothelial invasion. PLoS Pathog. 2012;8(6): e1002777. doi: 10.1371/journal.ppat.1002777 22761575

171. Sheldon JR, Skaar EP. Metals as phagocyte antimicrobial effectors. Current Opinion in Immunology. 2019;60: 1–9. doi: 10.1016/j.coi.2019.04.002 31063946

172. Brown AJP, Budge S, Kaloriti D, Tillmann A, Jacobsen MD, Yin Z, et al. Stress adaptation in a pathogenic fungus. Journal of Experimental Biology. 2014;217(Pt 1): 144–155. doi: 10.1242/jeb.088930 24353214

173. Brown AJP, Gow NAR, Warris A, Brown GD. Memory in Fungal Pathogens Promotes Immune Evasion, Colonisation, and Infection. Trends in Microbiology. 2019;27(3): 219–230. Epub 30 Nov 2018. doi: 10.1016/j.tim.2018.11.001 30509563

174. Cavalheiro M, Teixeira MC. Candida Biofilms: Threats, Challenges, and Promising Strategies. Front Med. 2018;5: 28. doi: 10.3389/fmed.2018.00028 29487851

175. Soll DR, Daniels KJ. Plasticity of Candida albicans Biofilms. Microbiol Mol Biol Rev. 2016;80(3): 565–595. doi: 10.1128/MMBR.00068-15 27250770

176. Taff HT, Mitchell KF, Edward JA, Andes DR. Mechanisms of Candida biofilm drug resistance. Future Microbiology. 2013;8(10): 1325–1337. doi: 10.2217/fmb.13.101 24059922

177. Wuyts J, Van Dijck P, Holtappels M. Fungal persister cells: The basis for recalcitrant infections? PLoS Pathog. 2018;14(10): e1007301. doi: 10.1371/journal.ppat.1007301 30335865

178. Rossignol T, Ding C, Guida A, D’Enfert C, Higgins DG, Butler G. Correlation between biofilm formation and the hypoxic response in Candida parapsilosis. Eukaryot Cell. 2009;8(4): 550–559. doi: 10.1128/EC.00350-08 19151323

179. Zarnowski R, Westler WM, de Lacmbouh GA, Marita JM, Bothe JR, Bernhardt J, et al. Novel entries in a fungal biofilm matrix encyclopedia. mBio. 2014;5: e01333–14. doi: 10.1128/mBio.01333-14 25096878

180. Nobile CJ, Fox EP, Nett JE, Sorrells TR, Mitrovich QM, Hernday AD, et al. A recently evolved transcriptional network controls biofilm development in Candida albicans. Cell. 2012;148: 126–138. doi: 10.1016/j.cell.2011.10.048 22265407

181. Martínez-Gomariz M, Perumal P, Mekala S, Nombela C, Chaffin WLJ, Gil C. Proteomic analysis of cytoplasmic and surface proteins from yeast cells, hyphae, and biofilms of Candida albicans. Proteomics. 2009;9(8): 2230–2252. doi: 10.1002/pmic.200700594 19322777

182. Ene IV., Cheng SC, Netea MG, Brown AJP. Growth of Candida albicans cells on the physiologically relevant carbon source lactate affects their recognition and phagocytosis by immune cells. Infect Immun. 2013;81: 238–248. doi: 10.1128/IAI.01092-12 23115042

183. Chew SY, Ho KL, Cheah YK, Ng TS, Sandai D, Brown AJP, et al. Glyoxylate cycle gene ICL1 is essential for the metabolic flexibility and virulence of Candida glabrata. Sci Rep. 2019;9(1): 2843. doi: 10.1038/s41598-019-39117-1 30808979

184. Oliveira-Pacheco J, Alves R, Costa-Barbosa A, Cerqueira-Rodrigues B, Pereira-Silva P, Paiva S, et al. The role of Candida albicans transcription factor RLM1 in response to carbon adaptation. Front Microbiol. 2018;9: 1127. doi: 10.3389/fmicb.2018.01127 29896184