Roles of Candida albicans Aspartic Proteases in Host-Pathogen Interactions

  • Mariusz Gogol
  • Oliwia Bochenska
  • Marcin Zawrotniak
  • Justyna Karkowska-Kuleta
  • Dorota Zajac
  • Maria Rapala-KozikEmail author


Candida albicans—a common opportunistic fungal pathogen of humans—causes serious, disseminated invasive infections (candidiases) executed due to the action of several groups of virulence factors. One of the most critical is a family of secreted aspartic proteases involved in the destruction of host proteins and tissues. This chapter aims to characterize biochemical and structural properties of these enzymes that determine their functions and summarize their specific roles in the development and propagation of fungal infections. Candidal aspartic proteases deregulate the host biochemical homeostasis, by impairing the major proteolytic cascades such as the blood coagulation, the kallikrein-kinin system, and the complement system, by unleashing the activity of host proteases due to the degradation of specific endogenous inhibitors and by the inactivation of antimicrobial peptides and proteins produced by host cells. The degradation of important host proteins influences the fungal adhesion to the host cell surfaces, promotes the subsequent tissue damages, and enables the further dissemination of the pathogen. Confirmed multiple roles of candidal aspartic proteases in the host-pathogen interactions during candidiasis qualify these enzymes as promising potential targets for novel antifungal therapies.


Candida albicans Fungal infection Aspartic proteases (Saps) Protein degradation Host cell interaction Antibacterial peptides Kinins 



This work was supported in part by the National Science Centre of Poland (grant no. 571 UMO-2012/05/B/NZ1/00003 awarded to M.R.-K). Faculty of Biochemistry, Biophysics, and Biotechnology of Jagiellonian University is a partner of the Leading National Research Center (KNOW) supported by the Ministry of Science and Higher Education.


  1. 1.
    Yapar N (2014) Epidemiology and risk factors for invasive candidiasis. Ther Clin Risk Manag 10:95–105PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Horn DL, Neofytos D, Anaissie EJ et al (2009) Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 48:1695–1703PubMedCrossRefGoogle Scholar
  4. 4.
    Pana ZD, Farmaki E, Roilides E (2014) Host genetics and opportunistic fungal infections. Clin Microbiol Infect 20:1254–1264PubMedCrossRefGoogle Scholar
  5. 5.
    Eggimann P, Que YA, Revelly JP, Pagani JL (2015) Preventing invasive Candida infections. Where could we do better? J Hosp Infect 89:302–308PubMedCrossRefGoogle Scholar
  6. 6.
    Perlroth J, Choi B, Spellberg B (2007) Nosocomial fungal infections: epidemiology, diagnosis, and treatment. Med Mycol 45:321–346PubMedCrossRefGoogle Scholar
  7. 7.
    Kullberg BJ, Arendrup MC (2016) Invasive candidiasis. N Engl J Med 374:794–795PubMedGoogle Scholar
  8. 8.
    Gudlaugsson O, Gillespie S, Lee K et al (2003) Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 37:1172–1177PubMedCrossRefGoogle Scholar
  9. 9.
    Soll DR, Galask R, Schmid J et al (1991) Genetic dissimilarity of commensal strains of Candida spp. carried in different anatomical locations of the same healthy women. J Clin Microbiol 29:1702–1710PubMedPubMedCentralGoogle Scholar
  10. 10.
    Cannon RD, Chaffin WL (1999) Oral colonization by Candida albicans. Crit Rev Oral Biol Med 10:359–383PubMedCrossRefGoogle Scholar
  11. 11.
    Akpan A, Morgan R (2002) Oral candidiasis. Postgrad Med J 78:455–459PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Achkar JM, Fries BC (2010) Candida infections of the genitourinary tract. Clin Microbiol Rev 23:253–273PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Mendling W, Brasch J, Cornely OA et al (2015) Guideline: vulvovaginal candidosis (AWMF 015/072), S2k (excluding chronic mucocutaneous candidosis). Mycoses S1:1–15CrossRefGoogle Scholar
  14. 14.
    Patil S, Rao RS, Majumdar B, Anil S (2015) Clinical appearance of oral Candida infection and therapeutic strategies. Front Microbiol 6:1391PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Lewis RE (2009) Overview of the changing epidemiology of candidemia. Curr Med Res Opin 25:1732–1740PubMedCrossRefGoogle Scholar
  16. 16.
    Diekema D, Arbefeville S, Boyken L et al (2012) The changing epidemiology of healthcare-associated candidemia over three decades. Diagn Microbiol Infect Dis 73:45–48PubMedCrossRefGoogle Scholar
  17. 17.
    Arendrup MC (2013) Candida and candidaemia. Susceptibility and epidemiology. Dan Med J 60:B4698PubMedGoogle Scholar
  18. 18.
    Krcmery V, Barnes AJ (2002) Non-albicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect 50:243–260PubMedCrossRefGoogle Scholar
  19. 19.
    Karkowska-Kuleta J, Rapala-Kozik M, Kozik A (2009) Fungi pathogenic to humans: molecular bases of virulence of Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Acta Biochim Pol 56:211–224PubMedGoogle Scholar
  20. 20.
    Naglik JR, Moyes DL, Wächtler B, Hube B (2011) Candida albicans interactions with epithelial cells and mucosal immunity. Microbes Infect 13:963–976PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Polke M, Hube B, Jacobsen ID (2015) Candida survival strategies. Adv Appl Microbiol 91:139–235PubMedCrossRefGoogle Scholar
  22. 22.
    Liu Y, Filler SG (2011) Candida albicans Als3, a multifunctional adhesin and invasin. Eukaryot Cell 10:168–173PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Karkowska-Kuleta J, Kozik A (2014) Moonlighting proteins as virulence factors of pathogenic fungi, parasitic protozoa and multicellular parasites. Mol Oral Microbiol 29:270–283PubMedCrossRefGoogle Scholar
  24. 24.
    Karkowska-Kuleta J, Kozik A (2015) Cell wall proteome of pathogenic fungi. Acta Biochim Pol 62:339–351PubMedCrossRefGoogle Scholar
  25. 25.
    Naglik JR, Challacombe SJ, Hube B (2003) Candida albicans secreted aspartyl proteinases in virulence and pathogenesis. Microbiol Mol Biol Rev 67:400–428PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Schaller M, Borelli C, Korting HC, Hube B (2005) Hydrolytic enzymes as virulence factors of Candida albicans. Mycoses 48:365–377PubMedCrossRefGoogle Scholar
  27. 27.
    Hruskova-Heidingsfeldova O (2008) Secreted proteins of Candida albicans. Front Biosci 13:7227–7242PubMedCrossRefGoogle Scholar
  28. 28.
    Höfs S, Mogavero S, Hube B (2016) Interaction of Candida albicans with host cells: virulence factors, host defense, escape strategies, and the microbiota. J Microbiol 54:149–169PubMedCrossRefGoogle Scholar
  29. 29.
    Staib F (1965) Serum-proteins as nitrogen source for yeastlike fungi. Sabouraudia 4:187–193PubMedCrossRefGoogle Scholar
  30. 30.
    Aoki W, Kitahara N, Miura N et al (2011) Comprehensive characterization of secreted aspartic proteases encoded by a virulence gene family in Candida albicans. J Biochem 150:431–438PubMedCrossRefGoogle Scholar
  31. 31.
    Dos Santos ALS (2010) HIV aspartyl protease inhibitors as promising compounds against Candida albicans. World J Biol Chem 1:21–30PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Albrecht A, Felk A, Pichova I (2006) Glycosylphosphatidylinositol-anchored proteases of Candida albicans target proteins necessary for both cellular processes and host-pathogen interactions. J Biol Chem 281:688–694PubMedCrossRefGoogle Scholar
  33. 33.
    Silva NC, Nery JM, Dias ALT (2014) Aspartic proteinases of Candida spp.: role in pathogenicity and antifungal resistance. Mycoses 57:1–11PubMedCrossRefGoogle Scholar
  34. 34.
    Borelli C, Ruge E, Lee JH et al (2008) X-ray structures of Sap1 and Sap5: structural comparison of the secreted aspartic proteinases from Candida albicans. Proteins 72:1308–1319PubMedCrossRefGoogle Scholar
  35. 35.
    Cutfield SM, Dodson EJ, Anderson BF et al (1995) The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors. Structure 3:1261–1271PubMedCrossRefGoogle Scholar
  36. 36.
    Abad-Zapatero C, Goldman R, Muchmore SW et al (1996) Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents. Protein Sci 5:640–652PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Behnen J, Koster H, Neudert G et al (2012) Experimental and computational active site mapping as a starting point to fragment-based lead discovery. Chem Med Chem 7:248–261PubMedCrossRefGoogle Scholar
  38. 38.
    Borelli C, Ruge E, Schaller M et al (2007) The crystal structure of the secreted aspartic proteinase 3 from Candida albicans and its complex with pepstatin A. Proteins 68:738–748PubMedCrossRefGoogle Scholar
  39. 39.
    Stewart K, Abad-Zapatero C (2001) Candida proteases and their inhibition: prospects for antifungal therapy. Curr Med Chem 8:941–948PubMedCrossRefGoogle Scholar
  40. 40.
    Monod M, Staib P, Borelli C (2013) Candidapepsin. In: Handbook of proteolytic enzymes, vol 1, pp 159–166Google Scholar
  41. 41.
    Delano WL (2006) The PyMol molecular graphics system. Delano Scientific LLC, San CarlosGoogle Scholar
  42. 42.
    Borg-von Zepelin M, Beggah S, Boggian K et al (1998) The expression of the secreted aspartyl proteinases Sap4 to Sap6 from Candida albicans in murine macrophages. Mol Microbiol 28:543–554PubMedCrossRefGoogle Scholar
  43. 43.
    Koelsch G, Tang J, Loy JA et al (2000) Enzymic characteristics of secreted aspartic proteases of Candida albicans. Biochim Biophys Acta 1480:117–131PubMedCrossRefGoogle Scholar
  44. 44.
    Bochenska O, Rapala-Kozik M, Wolak N et al (2016) The action of ten secreted aspartic proteases of pathogenic yeast Candida albicans on major human salivary antimicrobial peptide, histatin 5. Act Biochi Pol 63:1–8CrossRefGoogle Scholar
  45. 45.
    Smolenski G, Sullivan PA, Cutfield SM, Cutfield JF (1997) Analysis of secreted aspartic proteinases from Candida albicans: purification and characterization of individual Sap1, Sap2 and Sap3 isoenzymes. Microbiology 143:349–356PubMedCrossRefGoogle Scholar
  46. 46.
    Aoki W, Kitahara N, Miura N et al (2012) Candida albicans possesses Sap7 as a pepstatin A-insensitive secreted aspartic protease. PLoS ONE 7:1–9CrossRefGoogle Scholar
  47. 47.
    Schild L, Heyken A, de Groot PWJ et al (2011) Proteolytic cleavage of covalently linked cell wall proteins by Candida albicans Sap9 and Sap10. Eukaryot Cell 10:98–109PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Hube B (1998) Possible role of secreted proteinases in Candida albicans infections. Rev Iberoam Micol 15:65–68PubMedGoogle Scholar
  49. 49.
    Cheng SC, Joosten LA, Kullberg BJ et al (2012) Interplay between Candida albicans and the mammalian innate host defense. Infect Immun 80:1304–1313PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Zipfel PF, Hallström T, Riesbeck K (2013) Human complement control and complement evasion by pathogenic microbes–tipping the balance. Mol Immunol 56:152–160PubMedCrossRefGoogle Scholar
  51. 51.
    Naglik JR, Newport G, White TC et al (1999) In vivo analysis of secreted aspartyl proteinase expression in human oral candidiasis. Infect Immun 67:2482–2490PubMedPubMedCentralGoogle Scholar
  52. 52.
    Schaller M, Januschke E, Schackert C et al (2001) Different isoforms of secreted aspartyl proteinases (Sap) are expressed by Candida albicans during oral and cutaneous candidosis in vivo. J Med Microbiol 50:743–747PubMedCrossRefGoogle Scholar
  53. 53.
    Staniszewska M, Siennicka K, Pilat J et al (2012) Role of aspartic proteinases in Candida albicans virulence. Part II: Expression of SAP1-10 aspartic proteinase during Candida albicans infections in vivo. Post Mikrobiol 51:137–142Google Scholar
  54. 54.
    Naglik JR, Moyes D, Makwana J et al (2008) Quantitative expression of the Candida albicans secreted aspartyl proteinase gene family in human oral and vaginal candidiasis. Microbiology 154:3266–3280PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Staniszewska M, Bondarczyk MM, Siennicka K et al (2012) In vitro study of secreted aspartyl proteinases Sap1 to Sap3 and Sap4 to Sap6 expression in Candida albicans pleomorphic forms. Pol J Microbiol 61:247–256PubMedGoogle Scholar
  56. 56.
    Naglik JR, Rodgers C, Shirlaw PJ et al (2003) Differential expression of Candida albicans secreted aspartyl proteinase and phospholipase B genes in humans correlates with active oral and vaginal infections. J Infect Dis 188:469–479PubMedCrossRefGoogle Scholar
  57. 57.
    Schaller M, Korting HC, Schafer W et al (1998) Investigations on the regulation of secreted aspartyl proteases in a model of oral candidiasis in vivo. Mycoses 41:69–73PubMedCrossRefGoogle Scholar
  58. 58.
    Schaller M, Bein M, Korting HC et al (2003) The secreted aspartyl proteinases Sap1 and Sap2 cause tissue damage in an in vitro model of vaginal candidiasis based on reconstituted human vaginal epithelium. Infect Immun 71:3227–3234PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Schaller M, Hube B, Ollert MW et al (1999) In vivo expression and localization of Candida albicans secreted aspartyl proteinases during oral candidiasis in HIV-infected patients. J Invest Dermatol 112:383–386PubMedCrossRefGoogle Scholar
  60. 60.
    Staniszewska M, Bondaryk M, Malewski T, Kurzatkowski W (2014) Quantitative expression of Candida albicans aspartyl proteinase genes SAP7, SAP8, SAP9, SAP10 in human serum in vitro. Pol J Microbiol 63:15–20PubMedGoogle Scholar
  61. 61.
    Staniszewska M, Bondaryk M, Zukowski K, Chudy M (2015) Role of SAP7-10 and morphological regulators (EFG1, CPH1) in Candida albicans hypha formation and adhesion to colorectal carcinoma Caco-2. Pol J Microbiol 64:203–210PubMedCrossRefGoogle Scholar
  62. 62.
    Sanglard D, Hube B, Monod M et al (1997) A triple deletion of the secreted aspartyl proteinase genes SAP4, SAP5, and SAP6 of Candida albicans causes attenuated virulence. Infect Immun 65:3539–3546PubMedPubMedCentralGoogle Scholar
  63. 63.
    Hube B, Sanglard D, Odds FC et al (1997) Disruption of each of the secreted aspartyl proteinase genes SAP1, SAP2 and SAP3 of Candida albicans attenuates virulence. Infect Immun 65:3529–3538PubMedPubMedCentralGoogle Scholar
  64. 64.
    Kretschmar M, Felk A, Staib P et al (2002) Individual acid aspartic proteinases (Saps) 1–6 of Candida albicans are not essential for invasion and colonization of the gastrointestinal tract in mice. Microb Pathog 32:61–70PubMedCrossRefGoogle Scholar
  65. 65.
    Felk A, Kretschmar M, Albrecht A et al (2002) Candida albicans hyphal formation and the expression of the Efg1-regulated proteinases Sap4 to Sap6 are required for the invasion of parenchymal organs. Infect Immun 70:3689–3700PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Correia A, Lermann U, Teixeira L et al (2010) Limited role of secreted aspartyl proteinases Sap1 to Sap6 in Candida albicans virulence and host immune response in murine hematogenously disseminated candidiasis. Infect Immun 78:4839–4849PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Jackson BE, Wilhelmus KR, Hube B (2007) The role of secreted aspartyl proteinases in Candida albicans keratitis. Invest Ophthalmol Vis Sci 48:3559–3565PubMedCrossRefGoogle Scholar
  68. 68.
    Stringaro A, Crateri P, Pellegrini G et al (1997) Ultrastructural localization of the secretory aspartyl proteinase in Candida albicans cell wall in vitro and in experimentally infected rat vagina. Mycopathologia 137:95–105PubMedCrossRefGoogle Scholar
  69. 69.
    Hube B, Monod M, Schofield DA et al (1994) Expression of seven members of the gene family encoding secretory aspartyl proteinases in Candida albicans. Mol Microbiol 14:87–99PubMedCrossRefGoogle Scholar
  70. 70.
    Colina AR, Aumont F, Deslauriers N et al (1996) Evidence for degradation of gastrointestinal mucin by Candida albicans secretory aspartyl proteinase. Infect Immun 64:4514–4519PubMedPubMedCentralGoogle Scholar
  71. 71.
    Villar CC, Kashleva H, Nobile CJ et al (2007) Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor Rim101p and protease Sap5p. Infect Immun 75:2126–2135PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Morschhäuser J, Virkola R, Korhonen TK, Hacker J (1997) Degradation of human subendothelial extracellular matrix by proteinase-secreting Candida albicans. FEMS Microbiol Lett 153:349–355PubMedCrossRefGoogle Scholar
  73. 73.
    Ollert MW, Söhnchen R, Korting HC et al (1993) Mechanisms of adherence of Candida albicans to cultured human epidermal keratinocytes. Infect Immun 61:4560–4568PubMedPubMedCentralGoogle Scholar
  74. 74.
    Ray TL, Payne CD (1988) Scanning electron microscopy of epidermal adherence and cavitation in murine candidiasis: a role for Candida acid proteinase. Infect Immun 56:1942–1949PubMedPubMedCentralGoogle Scholar
  75. 75.
    Borg M, Rüchel R (1988) Expression of extracellular acid proteinase by proteolytic Candida spp. during experimental infection of oral mucosa. Infect Immun 56:626–631PubMedPubMedCentralGoogle Scholar
  76. 76.
    Rüchel R (1986) Cleavage of immunoglobulins by pathogenic yeasts of the genus Candida. Microbiol Sci 3:316–319PubMedGoogle Scholar
  77. 77.
    Marcotte H, Lavoie MC (1998) Oral microbial ecology and the role of salivary immunoglobulin A. Microbiol Mol Biol Rev 62:71–109PubMedPubMedCentralGoogle Scholar
  78. 78.
    Gropp K, Schild L, Schindler S et al (2009) The yeast Candida albicans evades human complement attack by secretion of aspartic proteases. Mol Immunol 47:465–475PubMedCrossRefGoogle Scholar
  79. 79.
    Luo S, Skerka C, Kurzai O, Zipfel PF (2013) Complement and innate immune evasion strategies of the human pathogenic fungus Candida albicans. Mol Immunol 56:161–169PubMedCrossRefGoogle Scholar
  80. 80.
    Svoboda E, Schneider AE, Sándor N et al (2015) Secreted aspartic protease 2 of Candida albicans inactivates factor H and the macrophage factor H-receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18). Immunol Lett 168:13–21PubMedCrossRefGoogle Scholar
  81. 81.
    Rapala-Kozik M, Karkowska-Kuleta J, Ryzanowska A et al (2010) Degradation of human kininogens with the release of kinin peptides by extracellular proteinases of Candida spp. Biol Chem 391:823–830PubMedCrossRefGoogle Scholar
  82. 82.
    Rüchel R (1983) On the renin-like activity of Candida proteinases and activation of blood coagulation in vitro. Zentralbl Bakteriol Mikrobiol Hyg A 255:368–379PubMedGoogle Scholar
  83. 83.
    Kaminishi H, Hamatake H, Cho T et al (1994) Activation of blood clotting factors by microbial proteinases. FEMS Microbiol Lett 121:327–332PubMedCrossRefGoogle Scholar
  84. 84.
    Frick IM, Björck L, Herwald H (2007) The dual role of the contact system in bacterial infectious disease. Thromb Haemost 98:497–502PubMedCrossRefGoogle Scholar
  85. 85.
    Cockcroft JR, Chowienczyk PJ, Brett SE, Ritter JM (1994) Effect of NG-monomethyl-L-arginine on kinin-induced vasodilation in the human forearm. Br J Clin Pharmacol 38:307–310PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Golias C, Charalabopoulos A, Stagikas D el al (2007) The kinin system-bradykinin: biological effects and clinical implications. Multiple role of the kinin system-bradykinin. Hippokratia 11:124–128Google Scholar
  87. 87.
    Imamura T, Tanase S, Szmyd G et al (2005) Induction of vascular leakage through release of bradykinin and a novel kinin by cysteine proteinases from Staphylococcus aureus. J Exp Med 201:1669–1676PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Wu Y (2015) Contact pathway of coagulation and inflammation. Thromb J 13:17PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lalmanach G, Naudin C, Lecaille F, Fritz H (2010) Kininogens: more than cysteine protease inhibitors and kinin precursors. Biochimie 92:1568–1579PubMedCrossRefGoogle Scholar
  90. 90.
    Kaminishi H, Tanaka M, Cho T et al (1990) Activation of the plasma kallikrein-kinin system by Candida albicans proteinase. Infect Immun 58:2139–2143PubMedPubMedCentralGoogle Scholar
  91. 91.
    Bras G, Bochenska O, Rapala-Kozik M et al (2012) Extracellular aspartic protease SAP2 of Candida albicans yeast cleaves human kininogens and releases proinflammatory peptides, Met-Lys-bradykinin and des-Arg(9)-Met-Lys-bradykinin. Biol Chem 393:829–839PubMedCrossRefGoogle Scholar
  92. 92.
    Kozik A, Gogol M, Bochenska O et al (2015) Kinin release from human kininogen by 10 aspartic proteases produced by pathogenic yeast Candida albicans. BMC Microbiol 15:60PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Rüchel R (1983) On the role of proteinases from Candida albicans in the pathogenesis of acronecrosis. Zentralbl Bakteriol Mikrobiol Hyg A 255:524–536PubMedGoogle Scholar
  94. 94.
    Kaminishi H, Miyaguchi H, Tamaki T et al (1995) Degradation of humoral host defense by Candida albicans proteinase. Infect Immun 63:984–988PubMedPubMedCentralGoogle Scholar
  95. 95.
    Tsushima H, Mine H, Kawakami Y et al (1994) Candida albicans aspartic proteinase cleaves and inactivates human epidermal cysteine proteinase inhibitor, cystatin A. Microbiology 140:167–171PubMedCrossRefGoogle Scholar
  96. 96.
    Gogol M, Ostrowska D, Klaga K et al (2016) Inactivation of α1-proteinase inhibitor by Candida albicans aspartic proteases favors the epithelial and endothelial cell colonization in the presence of neutrophil extracellular traps. Acta Biochim Pol 63:1163CrossRefGoogle Scholar
  97. 97.
    Zawrotniak M, Rapala-Kozik M (2013) Neutrophil extracellular traps (NETs)—formation and implications. Acta Biochim Pol 60:277–284PubMedGoogle Scholar
  98. 98.
    Moyes DL, Richardson JP, Naglik JR (2015) Candida albicans-epithelial interactions and pathogenicity mechanisms: scratching the surface. Virulence 6:338–346PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Wu H, Downs D, Ghosh K et al (2013) Candida albicans secreted aspartic proteases 4–6 induce apoptosis of epithelial cells by a novel Trojan horse mechanism. FASEB J 27:2132–2144PubMedCrossRefGoogle Scholar
  100. 100.
    Johansson AC, Appelqvist H, Nilsson C et al (2010) Regulation of apoptosis-associated lysosomal membrane permeabilization. Apoptosis 15:527–540PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Pietrella D, Rachini A, Pandey N et al (2010) The inflammatory response induced by aspartic proteases of Candida albicans is independent of proteolytic activity. Infect Immun 78:4754–4762PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Beauséjour A, Grenier D, Goulet JP, Deslauriers N (1998) Proteolytic activation of the interleukin-1beta precursor by Candida albicans. Infect Immun 66:676–681PubMedPubMedCentralGoogle Scholar
  103. 103.
    Pietrella D, Pandey N, Gabrielli E et al (2013) Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome. Eur J Immunol 43:679–692PubMedCrossRefGoogle Scholar
  104. 104.
    Jiménez-López C, Lorenz MC (2013) Fungal immune evasion in a model host-pathogen interaction: candida albicans versus macrophages. PLoS Pathog 9(11):e1003741PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Cheng SC, Sprong T, Joosten LA et al (2012) Complement plays a central role in Candida albicans-induced cytokine production by human PBMCs. Eur J Immunol 42:993–1004Google Scholar
  106. 106.
    Ran Y, Iwabuchi K, Yamazaki M et al (2013) Secreted aspartic proteinase from Candida albicans acts as a chemoattractant for peripheral neutrophils. J Dermatol Sci 72:191–193PubMedCrossRefGoogle Scholar
  107. 107.
    Hornbach A, Heyken A, Schild L et al (2009) The glycosylphosphatidylinositol-anchored protease Sap9 modulates the interaction of Candida albicans with human neutrophils. Infect Immun 77:5216–5224PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Pericolini E, Gabrielli E, Amacker M et al (2015) Secretory aspartyl proteinases cause vaginitis and can mediate vaginitis caused by Candida albicans in mice. MBio 6:e00724–15PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Gabrielli E, Sabbatini S, Roselletti E et al (2016) In vivo induction of neutrophil chemotaxis by secretory aspartyl proteinases of Candida albicans. Virulence 29:1–7Google Scholar
  110. 110.
    Brinkmann V, Reichard U, Goosmann C et al (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535CrossRefGoogle Scholar
  111. 111.
    Rapala-Kozik M, Bochenska O, Zawrotniak M et al (2015) Inactivation of the antifungal and immunomodulatory properties of human cathelicidin LL-37 by aspartic proteases produced by the pathogenic yeast Candida albicans. Infect Immun 83:2518–2530PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Meiller TF, Hube B, Schild L et al (2009) A novel immune evasion strategy of Candida albicans: proteolytic cleavage of a salivary antimicrobial peptide. PLoS ONE 4:e5039PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Vandamme D, Landuyt B, Luyten W, Schoofs L (2012) A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cell Immunol 280:22–35PubMedCrossRefGoogle Scholar
  114. 114.
    Bochenska O, Rapala-Kozik M, Wolak N et al (2015) Inactivation of human kininogen-derived antimicrobial peptides by secreted aspartic proteases produced by the pathogenic yeast Candida albicans. Biol Chem 396:1369–1375PubMedCrossRefGoogle Scholar
  115. 115.
    Frick IM, Akesson P, Herwald H et al (2006) The contact system—A novel branch of innate immunity generating antibacterial peptides. EMBO J 25:5569–5578PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Nordahl EA, Rydengård V, Mörgelin M, Schmidtchen A (2005) Domain 5 of high molecular weight kininogen is antibacterial. J Biol Chem 280:34832–34839PubMedCrossRefGoogle Scholar
  117. 117.
    Ganguly S, Mitchell AP (2011) Mucosal biofilm of Candida albicans. Curr Opin Microbiol 14:380–385PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Mendes A, Mores AU, Carvalho AP et al (2007) Candida albicans biofilms produce more secreted aspartyl protease than the planktonic cells. Biol Pharm Bull 30:1813–1815PubMedCrossRefGoogle Scholar
  119. 119.
    Xu H, Sobue T, Bertolini M, Thompson A, Dongari-Bagtzoglou A (2016) Streptocuccus oralis and Candida albicans synergistically activate calpain to degrade E-cadherin from oral epithelial junctions. J Infect Dis 13:pii:jiw201Google Scholar
  120. 120.
    Dutton LC, Jenkinson HF, Lamont RJ, Nobbs AH (2016) Role of Candida albicans secreted aspartyl protease Sap9 in interkingdom biofilm formation. Pathog Dis 74:pii:ftw005Google Scholar
  121. 121.
    Hrusková-Heidingsfeldová O, Dostál J, Majer F et al (2009) Two aspartic proteinases secreted by the pathogenic yeast Candida parapsilosis differ in expression pattern and catalytic properties. Biol Chem 390:259–268Google Scholar
  122. 122.
    Dostál J, Pecina A, Hrusková-Heidingsfeldová O et al (2015) Atomic resolution crystal structure of Sapp2p, a secreted aspartic protease from Candida parapsilosis. Acta Cryst D 71:2494–2504CrossRefGoogle Scholar
  123. 123.
    Vinterová Z, Sanda M, Dostál J et al (2011) Evidence for the presence of proteolytically active secreted aspartic proteinase 1 of Candida parapsilosis in the cell wall. Protein Sci 20:2004–2012PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Hrušková-Heidingsfeldová O, Dostál J, Hamal P et al (2001) Enzymological characterization of secreted proteinases from Candida parapsilosis and Candida lusitaniae. Collect Czech Chem Commun 66:1707–1719CrossRefGoogle Scholar
  125. 125.
    Dostál J, Brynda J, Hrusková-Heidingsfeldová O et al (2009) The crystal structure of the secreted aspartic protease 1 from Candida parapsilosis in complex with pepstatin A. J Struct Biol 167:145–152PubMedCrossRefGoogle Scholar
  126. 126.
    Horváth P, Nosanchuk JD, Hamari Z et al (2012) The identification of gene duplication and the role of secreted aspartyl proteinase 1 in Candida parapsilosis virulence. J Infect Dis 205:923–933PubMedCrossRefGoogle Scholar
  127. 127.
    Merkerová M, Dostál J, Hradilek M et al (2006) Cloning and characterization of Sapp2p, the second aspartic proteinase isoenzyme from Candida parapsilosis. FEMS Yeast Res 6:1018–1026PubMedCrossRefGoogle Scholar
  128. 128.
    Bras G, Bochenska O, Rapala-Kozik M et al (2013) Release of biologically active kinin peptides, Met-Lys-bradykinin and Leu-Met-Lys-bradykinin from human kininogens by two major secreted aspartic proteases of Candida parapsilosis. Peptides 48:114–123PubMedCrossRefGoogle Scholar
  129. 129.
    Parra-Ortega B, Cruz-Torres H, Villa-Tanaca L, Hernández-Rodríguez C (2009) Phylogeny and evolution of the aspartyl protease family from clinically relevant Candida species. Mem Inst Oswaldo Cruz 104:505–512PubMedCrossRefGoogle Scholar
  130. 130.
    Symersky J, Monod M, Foundling SI (1997) High-resolution structure of the extracellular aspartic proteinase from Candida tropicalis yeast. Biochemistry 36:12700–12710PubMedCrossRefGoogle Scholar
  131. 131.
    Zaugg C, Borg-Von Zepelin M, Reichard U et al (2001) Secreted aspartic proteinase family of Candida tropicalis. Infect Immun 69:405–412PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Kontoyiannis D, Vaziri I, Hanna H et al (2001) Risk factors for Candida tropicalis fungemia in patients with cancer. Clin Infect Dis 33:1676–1681PubMedCrossRefGoogle Scholar
  133. 133.
    Silva S, Negri M, Henriques M et al (2010) Silicone colonization by non-Candida albicans Candida species in the presence of urine. J Med Microbiol 59:747–754PubMedCrossRefGoogle Scholar
  134. 134.
    Okumura Y, Inoue N, Nikai T (2007) Isolation and characterization of a novel acid proteinase, tropiase, from Candida tropicalis IFO 0589. Nihon Ishinkin Gakkai Zasshi 48:19–25PubMedCrossRefGoogle Scholar
  135. 135.
    Chen YV, Rosli R, Fong SH et al (2012) Histopathological characteristics of experimental Candida tropicalis induced acute systemic candidiasis in BALB/c Mice. Int J Zool Res 1:12–22Google Scholar
  136. 136.
    Kaur R, Ma B, Cormack BP (2007) A family of glycosylphosphatidylinositol-linked aspartyl proteases is required for virulence of Candida glabrata. Proc Natl AcadSci USA 104:7628–7633CrossRefGoogle Scholar
  137. 137.
    Nguyen JT, Hamada Y, Kimura T, Kiso Y (2008) Design of potent aspartic protease inhibitors to treat various diseases. Arch Pharm 341:523–535CrossRefGoogle Scholar
  138. 138.
    Braga-Silva LA, Santos ALS (2011) Aspartic protease inhibitors as potential anti-Candida albicans drugs: impacts on fungal biology, virulence and pathogenesis. Curr Med Chem 18:2401–2419PubMedCrossRefGoogle Scholar
  139. 139.
    Santos ALS (2011) Aspartic proteases of human pathogenic fungi are prospective targets for the generation of novel and effective antifungal inhibitors. Curr Enz Inhib 7:96–118CrossRefGoogle Scholar
  140. 140.
    Bondaryk M, Kurzątkowski W, Staniszewska M (2013) Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development. Postępy Dermatol Alergol 30:293–301PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Kuriyama T, Williams DW, Lewis MA (2003) In vitro secreted aspartyl proteinase activity of Candida albicans isolated from oral diseases and healthy oral cavities. Oral Microbiol Immunol 18:405–407PubMedCrossRefGoogle Scholar
  142. 142.
    Schaller M, Schäfer W, Korting HC, Hube B (1998) Differential expression of secreted aspartyl proteinases in a model of human oral candidiosis and in patient samples from oral cavity. Mol Microbiol 29:605–615PubMedCrossRefGoogle Scholar
  143. 143.
    Lermann U, Morschhäuser J (2008) Secreted aspartic proteases are not required for invasion of reconstituted human epithelia by Candida albicans. Microbiol 154:3281–3295CrossRefGoogle Scholar
  144. 144.
    Rüchel R, Ritter B, Schaffrinski M (1990) Modulation of experimental systemic murine candidosis by intravenous pepstatin. Zentralbl Bakteriol Mikrobiol Hyg 273:391–403CrossRefGoogle Scholar
  145. 145.
    Cauda R, Tacconelli M, Tumbarello M et al (1999) Role of protease inhibitors in preventing recurrent oral candidosis in patients with HIV infection: a prospective case-control study. J Acquir Immun Defic Syndr 21:20–25CrossRefGoogle Scholar
  146. 146.
    Borg-Von Zeppelin M, Meyer I, Thomssen R et al (1999) HIV-protease inhibitors reduce cell adherence of Candida albicans strains by inhibition of yeast secreted aspartic proteases. J Investig Dermatol 113:747–751CrossRefGoogle Scholar
  147. 147.
    Cassone A, De Bernardis F, Torosantucci A et al (1999) In vitro and in vivo anticandidal activity of human immunodeficiency vírus protease inhibitors. J Infect Dis 180:448PubMedCrossRefGoogle Scholar
  148. 148.
    Pichova I, Pavlickova L, Dostal J et al (2001) Secreted aspartic proteases of Candida albicans, Candida tropicalis, Candida parapsilosis and Candida lusitaneae. Inhibition with peptidomimetic inhibitors. Eur J Biochem 268:2669–2677PubMedCrossRefGoogle Scholar
  149. 149.
    Santos A, Braga-Silva L (2013) Aspartic protease inhibitors: effective drugs against the human fungal pathogen Candida albicans. Mini Rev Med Chem 13:155–162PubMedCrossRefGoogle Scholar
  150. 150.
    De Bernardis F, Liu H, O’Mahony R et al (2007) Human domain antibodies against virulence traits of candida albicans inhibits fungus adherence to vaginal epithelium and protect against experimental vaginal candidiasis. J Infect Dis 195:149–157PubMedCrossRefGoogle Scholar
  151. 151.
    Fear G, Komarnytsky S, Raskin I (2007) Protease inhibitors and their peptidomimetic derivatives as potential drugs. Pharmacol Ther 113:354–368PubMedCrossRefGoogle Scholar
  152. 152.
    Cadicamo C, Mortier J, Wolber G et al (2013) Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogs addressing different secreted aspartic proteases of Candida albicans. Biochem Pharmacol 85:881–887PubMedCrossRefGoogle Scholar
  153. 153.
    Zielinska P, Staniszewska M, Bondaryk M et al (2015) Design and studies o multiple mechanism of anti-Candida activity of new potent-Trp-rich peptide dendrimers. Eur J Med Chem 105:106–119PubMedCrossRefGoogle Scholar
  154. 154.
    Höfling JF, Mardegan RC, Anibal PC et al (2011) Evaluation of antifungal activity of medicinal plant extracts against oral Candida albicans and proteinases. Mycopathologia 172:117–124PubMedCrossRefGoogle Scholar
  155. 155.
    Sato T, Nagai K, Shibazaki M et al (1994) Novel aspartyl protease inhibitors, YF-0200R-A and B. J Antibiot (Tokyo) 47:566–570CrossRefGoogle Scholar
  156. 156.
    Christopeit T, Øverbø K, Danielson H, Nilsen IW (2013) Efficient screening of marine, FRET extracts for protease inhibitors by combining fret based activity assays and surface plasmon resonance spectroscopy based binding assays. Mar Drugs 11:4279–4293PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Hajjar FHE, Jebali A, Hekmatimoghaddam S (2015) The inhibition of Candida albicans secreted aspartyl proteinase by triangular gold nanoparticles. Nanomedicine J 2:54–59Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Mariusz Gogol
    • 1
    • 2
  • Oliwia Bochenska
    • 2
  • Marcin Zawrotniak
    • 1
  • Justyna Karkowska-Kuleta
    • 1
  • Dorota Zajac
    • 2
  • Maria Rapala-Kozik
    • 1
    Email author
  1. 1.Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and BiotechnologyJagiellonian UniversityKrakowPoland
  2. 2.Department of Analytical BiochemistryFaculty of Biochemistry, Biophysics and BiotechnologyKrakowPoland

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