Exposure of Aspergillus fumigatus to caspofungin induces an oxidative stress response.
Abstract
Caspofungin is widely used for the treatment of systemic fungal infections and exerts its effect by disrupting b-glucan biosynthesis. The aim of the work presented here was to establish how Aspergillus fumigatus reacted following exposure to capsofungin. Exposure of A. fumigatus to 0.1 or 1.0 m g/ml caspofungin for 4 hours resulted in protein leakage from hyphae and the increased expression of a variety of proteins involved in the oxidative stress response (e.g. catalase, antibiotic response protein), virulence (e.g. Asp F3, 18kDa antigen) and homeostasis (e.g. glyceraldehyde 3-phosphate, translation elongation factor, ATP synthase F1). In addition there was an increase in the activity of catalase, glutathione reductase and superoxide dismutase in hyphae exposed to 0.1 m g/ml caspofungin for 1 hour. The results presented here indicate that when A. fumigatus is exposed to caspofungin there is increased expression of a number of proteins associated with virulence and the oxidative stress response, and the activity of detoxifying enzymes possibly in an attempt to circumvent the intracellular effects of the antifungal agent.
References
Abruzzo GK, Gill CJ, Flattery AM, et al. Efficacy of the echinocandin caspofungin against disseminated Aspergillosis and Candidiasis in cyclophosphamide- induced immunosuppressed mice. Antimicrob Agents Chemother 2000; 44: 2310-8.
Betts R, Glasmacher A, Maertens J, et al. Efficacy of caspofungin against Candida or Invasive Aspergillus infections in neutropenic patients. Cancer 2006;106: 466-73.
Brakhage AA, Langfelder K. Menacing mold: the molecular biology of Aspergillus fumigatus. Ann. Rev. Microbiol. 2002;56: 433-455.
Carberry S, Molloy E, Hammel S, O'Keeffe G, Jones GW, Kavanagh K, Doyle S. Gliotoxin effects on fungal growth: mechanisms and exploitation. Fungal Genet Biol. 2012; 49:302-12.
Castillo L, Calvo E, Martinez AI et al. A study of the Candida albicans cell wall proteome. Proteomics 2008; 8: 3871-3881.
Deresinski S, Stevens DA. Caspofungin. Clin Infect Dis 2003; 36: 1445-57.
Diaz-Arevalo D, Ito JI, Kalkum M. Protective effector cells of the recombinant Asp f3 Anti- Aspergillosis Vaccine. Front Microbiol 2012; 3: 299 – 307.
Denning DW. Echinocandin antifungal drugs. Lancet 2003; 362: 1142-51.
Eshwika A, Kelly J, Fallon JP, Kavanagh K. Exposure of Aspergillus fumigatus to caspofungin results in the release, and de novo biosynthesis, of gliotoxin. Med Mycol 2013; 51: 121-127.
Foster JG, Hess JL. Responses of superoxide dismutase and glutathione reductase activity in cotton leaf tissue to an atmosphere enriched in oxygen. Plant Physiol 1980; 66: 482-87.
Larsen B, White S. Antifungal effect of hydrogen peroxide on catalase-producing strains of Candida spp. Infect Dis Obst Gynecol 1995; 3: 73-78.
Kelly J, Kavanagh K. Proteomic analysis of proteins released from growth-arrested Candida albicans following exposure to caspofungin. Med. Mycol. 2010; 48: 598-605.
Kelly J, Rowan R, McCann M, Kavanagh K. Exposure to caspofungin activates Cap and Hog pathways in Candida albicans. Med Mycol. 2009; 47: 697 - 706.
Maertens J, Raad I, Petrikkos G, et al. (2004). Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis 2004; 39: 1563-71.
Munro CA, Selvaggini S, de Bruijn I et al.. The PKC, HOG and Ca2+ signalling pathways co- ordinately regulate chitin synthesis in Candida albicans. Mol Microbiol 2007; 63: 1399-1413.
Petraitiene R, Petraitis V, Groll AH, et al. Antifungal efficacy of caspofungin (MK-0991) in experimental pulmonary Aspergillosis in persistently neutropenic Rabbits: pharmacokinetics, drug disposition, and relationship to galactomannan antigenemia. Antimicrob Agents Chemother 2002; 46: 12-23.
Reinoso-Martin C, Schuller C, Schuetzer- Muehlbauer M, Kuchler K. The yeast protein kinase C cell integrity pathway mediates tolerance to the antifungal drug caspofungin through activation of Slt2p mitogen-activated protein kinase signaling. Eukaryot Cell 2003; 2: 1200-1210.
Reeves EP, Murphy T, Daly P, Kavanagh K. Amphotericin B enhances the synthesis and release of the immunosuppressive agent gliotoxin from the pulmonary pathogen Aspergillus fumigatus. J Med Microbiol 2004; 53: 719-725.
Rementeria A, LoÌpez-Molina N, Ludwig A, Vivanco AB, Bikandi J, PontoÌn J, Garaizar J. Genes and molecules involved in Aspergillus fumigatus virulence. Rev Iberoam Micol. 2005; 22:1-23.
Sarria JC, Bradley JC, Habash R, et al. Candida glabrata endophthalmitis treated successfully with caspofungin. Clin Infect Dis 2005; 40: e46-8.
Schrettl, M, Carberry, S, Kavanagh, K, Haas, H, Jones GW, O‚Brien J, Stephens J, Fenelon O, Nolan A and Doyle, S. (2010) Self-Protection against Gliotoxin- A Component of the Gliotoxin Biosynthetic Cluster, GliT, Completely Protects Aspergillus fumigatus Against Exogenous Gliotoxin. PLOS Pathogens. June 2010 Issue 6.
Shevchenko A, Tomas H, Havlis J, Olsen JV, Mann M. In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat Protoc 2006; 1: 2856-2860.
Singh N, Husain S, the AST Infectious Diseases Community of Practice. Invasive Aspergillosis in solid organ Transplant recipients. Amer J. Transplant, 2009; 9: 180-191.
Stevens DA, Ichinomiya M, Koshi Y, Horiuchi H. Escape of Candida from caspofungin inhibition at concentrations above the MIC (Paradoxical Effect) accomplished by increased cell wall chitin; evidence for b-1,6-glucan synthesis inhibition by caspofungin. Antimicrob Agents Chemother 2006; 50: 3160-3161.
Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ. Azole resistance in Aspergillus fumigatus: a side effect of environmental fungicide use. Lancet Infect Dis. 2009; 9: 789-795.
V onberg R-P , Gastmeier P . Nosocomial aspergillosis in outbreak settings. J. Hosp Infect. 2009; 63: 246-254
Walker LA, Munro CA, de Bruijn I et al. Stimulation of chitin synthesis rescues Candida albicans from echinocandins. PLoS Pathog 2008; 4: e1000040.
Walsh TJ, Teppler H, Donowitz, GR, et al. Caspofungin versus liposomal Amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004; 351: 1391-402.
Wheeler RT, Fink GR. A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog 2006; 2: 328-339.
Wheeler RT, Kombe D, Agarwala SD, Fink GR. Dynamic, morphotype-specific Candida albicans β- glucan exposure during infection and drug treatment. PLoS Pathog 2008; 4 12: e1000227.
Schrettl M, Carberry S, Kavanagh K, Haas H, Jones GW, O’Brien J, Stephens J, Fenelon O, Nolan A, Doyle, S. Self-Protection against gliotoxin- A component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLOS Pathogens. 2010; 6, e1000952.
Lessing F, Kniemeyer O, Wozniok I, Loeffler J, Kurzai O, Haertl A, Brakhage, A. The Aspergillus fumigatus transcriptional regulator AfYap1 represents the major regulator for defense against reactive oxygen intermediates but is dispensable for pathogenicity in an intranasal mouse infection model. Eukaryot. Cell. 2007; 6:2290–2302.
Betts R, Glasmacher A, Maertens J, et al. Efficacy of caspofungin against Candida or Invasive Aspergillus infections in neutropenic patients. Cancer 2006;106: 466-73.
Brakhage AA, Langfelder K. Menacing mold: the molecular biology of Aspergillus fumigatus. Ann. Rev. Microbiol. 2002;56: 433-455.
Carberry S, Molloy E, Hammel S, O'Keeffe G, Jones GW, Kavanagh K, Doyle S. Gliotoxin effects on fungal growth: mechanisms and exploitation. Fungal Genet Biol. 2012; 49:302-12.
Castillo L, Calvo E, Martinez AI et al. A study of the Candida albicans cell wall proteome. Proteomics 2008; 8: 3871-3881.
Deresinski S, Stevens DA. Caspofungin. Clin Infect Dis 2003; 36: 1445-57.
Diaz-Arevalo D, Ito JI, Kalkum M. Protective effector cells of the recombinant Asp f3 Anti- Aspergillosis Vaccine. Front Microbiol 2012; 3: 299 – 307.
Denning DW. Echinocandin antifungal drugs. Lancet 2003; 362: 1142-51.
Eshwika A, Kelly J, Fallon JP, Kavanagh K. Exposure of Aspergillus fumigatus to caspofungin results in the release, and de novo biosynthesis, of gliotoxin. Med Mycol 2013; 51: 121-127.
Foster JG, Hess JL. Responses of superoxide dismutase and glutathione reductase activity in cotton leaf tissue to an atmosphere enriched in oxygen. Plant Physiol 1980; 66: 482-87.
Larsen B, White S. Antifungal effect of hydrogen peroxide on catalase-producing strains of Candida spp. Infect Dis Obst Gynecol 1995; 3: 73-78.
Kelly J, Kavanagh K. Proteomic analysis of proteins released from growth-arrested Candida albicans following exposure to caspofungin. Med. Mycol. 2010; 48: 598-605.
Kelly J, Rowan R, McCann M, Kavanagh K. Exposure to caspofungin activates Cap and Hog pathways in Candida albicans. Med Mycol. 2009; 47: 697 - 706.
Maertens J, Raad I, Petrikkos G, et al. (2004). Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis 2004; 39: 1563-71.
Munro CA, Selvaggini S, de Bruijn I et al.. The PKC, HOG and Ca2+ signalling pathways co- ordinately regulate chitin synthesis in Candida albicans. Mol Microbiol 2007; 63: 1399-1413.
Petraitiene R, Petraitis V, Groll AH, et al. Antifungal efficacy of caspofungin (MK-0991) in experimental pulmonary Aspergillosis in persistently neutropenic Rabbits: pharmacokinetics, drug disposition, and relationship to galactomannan antigenemia. Antimicrob Agents Chemother 2002; 46: 12-23.
Reinoso-Martin C, Schuller C, Schuetzer- Muehlbauer M, Kuchler K. The yeast protein kinase C cell integrity pathway mediates tolerance to the antifungal drug caspofungin through activation of Slt2p mitogen-activated protein kinase signaling. Eukaryot Cell 2003; 2: 1200-1210.
Reeves EP, Murphy T, Daly P, Kavanagh K. Amphotericin B enhances the synthesis and release of the immunosuppressive agent gliotoxin from the pulmonary pathogen Aspergillus fumigatus. J Med Microbiol 2004; 53: 719-725.
Rementeria A, LoÌpez-Molina N, Ludwig A, Vivanco AB, Bikandi J, PontoÌn J, Garaizar J. Genes and molecules involved in Aspergillus fumigatus virulence. Rev Iberoam Micol. 2005; 22:1-23.
Sarria JC, Bradley JC, Habash R, et al. Candida glabrata endophthalmitis treated successfully with caspofungin. Clin Infect Dis 2005; 40: e46-8.
Schrettl, M, Carberry, S, Kavanagh, K, Haas, H, Jones GW, O‚Brien J, Stephens J, Fenelon O, Nolan A and Doyle, S. (2010) Self-Protection against Gliotoxin- A Component of the Gliotoxin Biosynthetic Cluster, GliT, Completely Protects Aspergillus fumigatus Against Exogenous Gliotoxin. PLOS Pathogens. June 2010 Issue 6.
Shevchenko A, Tomas H, Havlis J, Olsen JV, Mann M. In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat Protoc 2006; 1: 2856-2860.
Singh N, Husain S, the AST Infectious Diseases Community of Practice. Invasive Aspergillosis in solid organ Transplant recipients. Amer J. Transplant, 2009; 9: 180-191.
Stevens DA, Ichinomiya M, Koshi Y, Horiuchi H. Escape of Candida from caspofungin inhibition at concentrations above the MIC (Paradoxical Effect) accomplished by increased cell wall chitin; evidence for b-1,6-glucan synthesis inhibition by caspofungin. Antimicrob Agents Chemother 2006; 50: 3160-3161.
Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ. Azole resistance in Aspergillus fumigatus: a side effect of environmental fungicide use. Lancet Infect Dis. 2009; 9: 789-795.
V onberg R-P , Gastmeier P . Nosocomial aspergillosis in outbreak settings. J. Hosp Infect. 2009; 63: 246-254
Walker LA, Munro CA, de Bruijn I et al. Stimulation of chitin synthesis rescues Candida albicans from echinocandins. PLoS Pathog 2008; 4: e1000040.
Walsh TJ, Teppler H, Donowitz, GR, et al. Caspofungin versus liposomal Amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004; 351: 1391-402.
Wheeler RT, Fink GR. A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog 2006; 2: 328-339.
Wheeler RT, Kombe D, Agarwala SD, Fink GR. Dynamic, morphotype-specific Candida albicans β- glucan exposure during infection and drug treatment. PLoS Pathog 2008; 4 12: e1000227.
Schrettl M, Carberry S, Kavanagh K, Haas H, Jones GW, O’Brien J, Stephens J, Fenelon O, Nolan A, Doyle, S. Self-Protection against gliotoxin- A component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLOS Pathogens. 2010; 6, e1000952.
Lessing F, Kniemeyer O, Wozniok I, Loeffler J, Kurzai O, Haertl A, Brakhage, A. The Aspergillus fumigatus transcriptional regulator AfYap1 represents the major regulator for defense against reactive oxygen intermediates but is dispensable for pathogenicity in an intranasal mouse infection model. Eukaryot. Cell. 2007; 6:2290–2302.
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Published
2018-06-26
How to Cite
Exposure of Aspergillus fumigatus to caspofungin induces an oxidative stress response. (2018). Lebda Medical Journal, 4(1), 140–147. Retrieved from https://lebmedj.elmergib.edu.ly/index.php/LMJ/article/view/73
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