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Abstract

The aim of this work was to characterize the response of to atorvastatin, and to assess its antifungal capability.

The effect of atorvastatin on the growth and viability of was assessed. The ability of the statin to alter cell permeability was quantified by measuring amino acid and protein leakage. The response of to atorvastatin was assessed using label-free quantitative proteomics. The antifungal activity of atorvastatin was assessed using larvae infected with .

Atorvastatin inhibited the growth of . The atorvastatin-treated cells showed lower ergosterol levels than the controls, demonstrated increased calcofluor staining and released elevated quantities of amino acids and protein. Larvae infected with showed a survival rate of 18.1±4.2 % at 144 h. In contrast, larvae administered atorvastatin (9.09 mg kg) displayed a survival rate of 60.2±6.4 % (<0.05). Label-free quantitative proteomics identified 1575 proteins with 2 or more peptides and 465 proteins were differentially abundant (<0.05). There was an increase in the abundance of enzymes with oxidoreductase and hydrolase activity in atorvastatin-treated cells, and squalene monooxygenase (4.52-fold increase) and lanosterol synthase (2.84-fold increase) were increased in abundance. Proteins such as small heat shock protein 21 (−6.33-fold) and glutathione peroxidase (−2.05-fold) were reduced in abundance.

The results presented here indicate that atorvastatin inhibits the growth of and is capable of increasing the survival of larvae infected with .

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2019-08-28
2024-04-16
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References

  1. Mayer FL, Wilson D, Hube B. Candida albicans pathogenicity mechanisms. Virulence 2013; 4:119–128 [View Article]
    [Google Scholar]
  2. Naglik JR, Challacombe SJ, Hube B. Candida albicans secreted aspartyl proteinases in virulence and pathogenesis. Microbiol Mol Biol Rev 2003; 67:400–428 [View Article]
    [Google Scholar]
  3. Calderone RA, Fonzi WA. Virulence factors of Candida albicans . Trends Microbiol 2001; 9:327–335 [View Article]
    [Google Scholar]
  4. Scorzoni L, de Paula e Silva ACA, Marcos CM, Assato PA, de Melo WCMA et al. Antifungal therapy: new advances in the understanding and treatment of mycosis. Front Microbiol 2017; 08: [View Article]
    [Google Scholar]
  5. Nyilasi I, Kocsubé S, Krizsán K, Galgóczy L, Pesti M et al. In vitro synergistic interactions of the effects of various statins and azoles against some clinically important fungi. FEMS Microbiol Lett 2010; 307:175–184 [View Article]
    [Google Scholar]
  6. Galgóczy L. Statins as antifungal agents. World J Clin Infect Dis 2011; 1:4 [View Article]
    [Google Scholar]
  7. Macreadie IG, Johnson G, Schlosser T, Macreadie PI. Growth inhibition of Candida species and Aspergillus fumigatus by statins. FEMS Microbiol Lett 2006; 262:9–13 [View Article]
    [Google Scholar]
  8. Westermeyer C, Macreadie IG. Simvastatin reduces ergosterol levels, inhibits growth and causes loss of mtDNA in Candida glabrata . FEMS Yeast Res 2007; 7:436–441 [View Article]
    [Google Scholar]
  9. Sun H-Y, Singh N. Antimicrobial and immunomodulatory attributes of statins: relevance in solid-organ transplant recipients. Clin Infect Dis 2009; 48:745–755 [View Article]
    [Google Scholar]
  10. Spanakis EK, Kourkoumpetis TK, Livanis G, Peleg AY, Mylonakis E. Statin therapy and decreased incidence of positive Candida cultures among patients with type 2 diabetes mellitus undergoing gastrointestinal surgery. Mayo Clin Proc 2010; 85:1073–1079 [View Article]
    [Google Scholar]
  11. Donnino MW, Cocchi MN, Howell M, Clardy P, Talmor D et al. Statin therapy is associated with decreased mortality in patients with infection. Acad Emerg Med 2009; 16:230–234 [View Article]
    [Google Scholar]
  12. Dobesh PP, Klepser DG, McGuire TR, Morgan CW, Olsen KM. Reduction in mortality associated with statin therapy in patients with severe sepsis. Pharmacotherapy 2009; 29:621–630 [View Article]
    [Google Scholar]
  13. Kruger PS. Statins: the next anti-endotoxin. Crit Care Resusc 2006; 8:223–226
    [Google Scholar]
  14. Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci 2002; 23:482–487 [View Article]
    [Google Scholar]
  15. Sheehan G, Nagl M, Kavanagh K. Exposure to N-chlorotaurine induces oxidative stress responses in Aspergillus fumigatus . J Med Microbiol 2019; 68:279288 [View Article]
    [Google Scholar]
  16. Arthington-Skaggs BA, Jradi H, Desai T, Morrison CJ. Quantitation of ergosterol content: novel method for determination of fluconazole susceptibility of Candida albicans . J Clin Microbiol 1999; 37:3332–3337
    [Google Scholar]
  17. Sheehan G, Bergsson G, McElvaney NG, Reeves EP, Kavanagh K. The human cathelicidin antimicrobial peptide LL-37 promotes the growth of the pulmonary pathogen Aspergillus fumigatus . Infect Immun 2018; IAI:00097–18
    [Google Scholar]
  18. Murphy AR, Kavanagh KA. Adherence of clinical isolates of Saccharomyces cerevisiae to buccal epithelial cells. Med Mycol 2001; 39:123–127 [View Article]
    [Google Scholar]
  19. Sheehan G, Clarke G, Kavanagh K. Characterisation of the cellular and proteomic response of Galleria mellonella larvae to the development of invasive aspergillosis. BMC Microbiol 2018; 18:1–11 [View Article]
    [Google Scholar]
  20. Sheehan G, Kavanagh K. Analysis of the early cellular and humoral responses of Galleria mellonella larvae to infection by Candida albicans . Virulence 2018; 9:163–172 [View Article]
    [Google Scholar]
  21. Côté RG, Griss J, Dianes JA, Wang R, Wright JC et al. The proteomics identification (pride) converter 2 framework: an improved suite of tools to facilitate data submission to the pride database and the ProteomeXchange Consortium. Mol Cell Proteomics 2012; 11:1682–1689 [View Article]
    [Google Scholar]
  22. Manzoni M, Rollini M. Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Applied Microbiology and Biotechnology 2002; 58:555–564
    [Google Scholar]
  23. Ramkumar S, Raghunath A, Raghunath S. Statin therapy: review of safety and potential side effects. Acta Cardiologica Sinica 2016; 32:631–639
    [Google Scholar]
  24. Chow SC. Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases. Arch Immunol Ther Exp 2009; 57:243–251 [View Article]
    [Google Scholar]
  25. Zeiser R. Immune modulatory effects of statins. Immunology 2018; 154:69–75 [View Article]
    [Google Scholar]
  26. Forero-Peña DA, Gutierrez FRS. Statins as modulators of regulatory T-cell biology. Mediators Inflamm 2013; 2013:16708610 [View Article]
    [Google Scholar]
  27. Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med 2001; 5:378–387 [View Article]
    [Google Scholar]
  28. Song J, Zhai P, Zhang Y, Zhang C, Sang H et al. The Aspergillus fumigatus damage resistance protein family coordinately regulates ergosterol biosynthesis and azole susceptibility. MBio 2016; 7: [View Article]
    [Google Scholar]
  29. Pendrak ML, Klotz SA. Adherence of Candida albicans to host cells. FEMS Microbiology Letters 1995; 129:103–113
    [Google Scholar]
  30. Brown AJP, Leach MD, Nicholls S. The relevance of heat shock regulation in fungal pathogens of humans. Virulence 2010; 1:330–332 [View Article]
    [Google Scholar]
  31. Pella D, Rybar R, Mechirova V. Pleiotropic effects of statins. Acta Cardiologica Sinica 2005; 21:190–198
    [Google Scholar]
  32. Liao JK. Isoprenoids as mediators of the biological effects of statins. J Clin Invest 2002; 110:285–288 [View Article]
    [Google Scholar]
  33. Ghittoni R, Patrussi L, Pirozzi K, Pellegrini M, Lazzerini PE et al. Simvastatin inhibits T-cell activation by selectively impairing the function of Ras superfamily GTPases. Faseb J 2005; 19:605–607 [View Article]
    [Google Scholar]
  34. Cordle A, Koenigsknecht-Talboo J, Wilkinson B, Limpert A, Landreth G. Mechanisms of statin-mediated inhibition of small G-protein function. J Biol Chem 2005; 280:34202–34209 [View Article]
    [Google Scholar]
  35. Brennan M, Thomas DY, Whiteway M, Kavanagh K. Correlation between virulence of Candida albicans mutants in mice and Galleria mellonella larvae. FEMS Immunol Med Microbiol 2002; 34:153–157 [View Article]
    [Google Scholar]
  36. Fuchs BB, Mylonakis E. Using non-mammalian hosts to study fungal virulence and host defense. Curr Opin Microbiol 2006; 9:346–351 [View Article]
    [Google Scholar]
  37. Maurer E, Browne N, Surlis C, Jukic E, Moser P et al. Galleria mellonella as a host model to study Aspergillus terreus virulence and amphotericin B resistance. Virulence 2015; 6:591–598 [View Article]
    [Google Scholar]
  38. Kavanagh K, Sheehan G. The use of Galleria mellonella larvae to identify novel antimicrobial agents against fungal species of medical interest. J Fungi 2018; 4:113 [View Article]
    [Google Scholar]
  39. Rahal EA, Constantin WN, Zeidan N, Abdelnoor AM. Atorvastatin reduces the survival of Candida albicans-Infected BALB/c mice. Front Microbiol 2015; 6:1474 [View Article]
    [Google Scholar]
  40. Tashiro M, Kimura S, Tateda K, Saga T, Ohno A et al. Pravastatin inhibits farnesol production in Candida albicans and improves survival in a mouse model of systemic candidiasis. Med Mycol 2012
    [Google Scholar]
  41. Cuervo G, Garcia-Vidal C, Nucci M, Puchades F, Fernández-Ruiz M et al. Effect of statin use on outcomes of adults with candidemia. PLoS One 2013; 8:e77317 [View Article]
    [Google Scholar]
  42. Forrest GN, Kopack AM, Perencevich EN. Statins in candidemia: clinical outcomes from a matched cohort study. BMC Infect Dis 2010; 10:152 [View Article]
    [Google Scholar]
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