Cytotoxic effect of Gliotoxin from Candida spp. isolated from clinical sources against cancer and normal cell lines

Noorulhuda Ojaimi Mahdi Al-Dahlaki; Safaa Al-Deen Ahmed Shanter Al-Qaysi

doi:10.32007/jfacmedbagdad.2078

Authors

Noorulhuda Ojaimi Mahdi Al-Dahlaki جامعة بغداد /علوم البنات https://orcid.org/0009-0007-8027-9564
Safaa Al-Deen Ahmed Shanter Al-Qaysi Department of Biology, College of Science for Girls, University of Baghdad https://orcid.org/0000-0002-5531-9532

DOI:

https://doi.org/10.32007/jfacmedbagdad.2078

Keywords:

Candida albicans, gliotoxin, HPLC, cytotoxicity

Abstract

Background: Invasive fungal infections have become more common during the past two decades. Candida species are the most common human fungal infections. Internal injuries characterize these infections because of virulence factors, such as gliotoxin, which is a fungal toxin that is thought to be antibacterial, antifungal, and antiviral.

Objectives: To test the ability of Candida species obtained from clinical sources to produce gliotoxin as a virulence factor and investigate its cytotoxicity effects against some selected cell lines.

Materials and Methods: One hundred and ten clinical isolates of Candida species were obtained from patients attending hospitals in Baghdad from September 2021 to March 2022. They were diagnosed and characterized by routine laboratory methods and cultures. The capability of Candida isolates to secrete the gliotoxin was tested and measured by analytical methods. The cytotoxicity of produced gliotoxin was applied against normal and cancer cell lines.

Results: The 110 yeast isolates were diagnosed and identified as follows: Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, Candida Krusei, Candida kefyr, Candida lusitaniae, Candida rugosa. Twenty-eight Candida isolates showed gliotoxin production. The cytotoxicity effects of gliotoxin were reported against lymphocytes and AMGM and AMJ13 cell lines in different concentrations. The highest cytotoxic effect was noticed in the concentration of 400 µg/mL of gliotoxin.

Conclusion: The results indicated that the pathogenicity of Candida was distributed among all ages, both sexes, and several types of sources of clinical isolates. Gliotoxin had an effect on normal and cancer cells.

Received: Feb., 2023

Accepted: Aug. 2023

Published: Oct. 2023

Downloads

Download data is not yet available.

References

Bongomin F, Gago S, Oladele RO, Denning DW. Global and multi-national prevalence of fungal diseases—estimate precision. Journal of fungi. 2017 Oct 18;3(4):57. https://doi.org/10.3390/jof3040057

Rodrigues ML, Nosanchuk JD. Fungal diseases as neglected pathogens: A wake-up call to public health officials. InAdvances in Clinical Immunology, Medical Microbiology, COVID-19, and Big Data 2021 Dec 22 (pp. 399-411). Jenny Stanford Publishing.

https://doi.org/10.1371/journal.pntd.0007964

Perlroth J, Choi B, Spellberg B. Nosocomial fungal infections: Epidemiology, diagnosis, and treatment. Medical mycology. 2007 Jun 1;45(4):321-46. https://doi.org/10.1080/13693780701218689

Brunke S, Mogavero S, Kasper L, Hube B. Virulence factors in fungal pathogens of man. Current opinion in microbiology. 2016 Aug 1;32:89-95. https://doi.org/10.1016/j.mib.2016.05.010

Pfaller MA, Diekema DJ. Rare and emerging opportunistic fungal pathogens: concern for resistance beyond Candida albicans and Aspergillus fumigatus. Journal of clinical microbiology. 2004 Oct;42(10):4419-31.

https://doi.org/10.1128/jcm.42.10.4419-4431.2004

Al-Dahlaki NO, Al SA. Production and Identification of Secondary Metabolite Gliotoxin-Like Substance Using Clinical Isolates of Candida spp. https://doi.org/10.48022/mbl.2209.09007

Rudenko P, Vatnikov Y, Sachivkina N, Rudenko A, Kulikov E, Lutsay V, et al. Search for promising strains of probiotic microbiota isolated from different biotopes of healthy cats for use in the control of surgical infections. Pathogens. 2021 May 28;10(6):667. https://doi.org/10.3390/pathogens10060667

Gardiner DM, Waring P, Howlett BJ. The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis. Microbiology. 2005 Apr;151(4):1021-32. https://doi.org/10.1099/mic.0.27847-0

Mayer FL, Wilson D, andHube B. Candida albicans pathogenicity mechanisms. Virulence.2013 4: 119-128. https://doi.org/10.4161/viru.22913

Sheppard DC, Locas MC, Restieri C, Laverdiere M. Utility of the germ tube test for direct identification of Candida albicans from positive blood culture bottles. Journal of Clinical Microbiology. 2008 Oct;46(10):3508-9. https://doi.org/10.1128/jcm.01113-08

Singh M, Chakraborty A. Antifungal drug resistance among candida albicans and Non-albicans candida species isolates from a tertiary care centre at allahabad. J Antimicrob Agents. 2017;3(150):2472-1212.

https://doi:10.4172/2472-1212.1000150

Böttcher B, Pöllath C, Staib P, Hube B, Brunke S. Candida species rewired hyphae developmental programs for chlamydospore formation. Frontiers in microbiology. 2016 Oct 27;7:1697.https://doi.org/10.3389/fmicb.2016.01697

Al-Tekreeti AR, Al-Halbosiy MM, Dheeb BI, Hashim AJ, Al-Zuhairi AF, Mohammad FI. Molecular identification of clinical Candida isolates by simple and randomly amplified polymorphic DNA-PCR. Arabian Journal for Science and Engineering. 2018 Jan;43:163-70.

https://doi.10.1007/s13369-017-2762-1

Kupfahl C, Pink D, Friedrich K, Zurbrügg HR, Neuss M, Warnecke C, et al. Angiotensin II directly increases transforming growth factor β1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovascular research. 2000 Jun 1;46(3):463-75. https://doi.org/10.1016/S0008-6363(00)00037-7

Paterson RR, Bridge PD. Biochemical techniques for filamentous fungi. International Mycological Institute, Bakeham Lane, Egham TW20 9TY, UK.; 1994.

Sael HA, Hamad Mohammed A, Maher AS, Muhammed HG. Detection of Gliotoxin as virulence factor in Aspergillus fumigatus.

Nouri MA, Al-Halbosiy MM, Dheeb BI, Hashim AJ. Cytotoxicity and genotoxicity of gliotoxin on human lymphocytes in vitro. Journal of King Saud University-Science. 2015 Jul 1;27(3):193-197.

https://doi.org/10.1016/j.jksus.2014.12.005

Bertling A, Niemann S, Uekötter A, Fegeler W, Lass-Flörl C, von Eiff C, et al. Candida albicans and its metabolite gliotoxin inhibit platelet function via interaction with thiols. Thrombosis and haemostasis. 2010;104(08):270-8. https://doi.10.1160/TH09-11-0769

Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, et al. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994 Sep 23;78(6):1039-49.

https://doi.org/10.1016/0092-8674(94)90278-X

Wang B, Relling MV, Storm MC, Woo MH, Ribeiro R, Pui CH, et al. Evaluation of immunologic crossreaction of antiasparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients. Leukemia. 2003 Aug;17(8):1583-8. https://doi.org/10.1038/sj.leu.2403011

Al-Shammari AM, Alshami MA, Umran MA, Almukhtar AA, Yaseen NY, Raad K, et al. Establishment and characterization of a receptor-negative, hormone-nonresponsive breast cancer cell line from an Iraqi patient. Breast Cancer: Targets and Therapy. 2015;7:223.

https://doi.org/10.2147/BCTT.S74509

Vandersickel V, Slabbert J, Thierens H, Vral A. Comparison of the colony formation and crystal violet cell proliferation assays to determine cellular radiosensitivity in a repair-deficient MCF10A cell line. Radiation measurements. 2011 Jan 1;46(1):72-5.

https://doi.org/10.1016/j.radmeas.2010.08.003

SPSS I. Corp Ibm SPSS statistics for windows, version 26.0. Armonk, NY: IBM Corp, Released. 2018.

Shin YJ, Shannon LJ, Bundy A, Coll M, Aydin K, Bez N, et al. Using indicators for evaluating, comparing, and communicating the ecological status of exploited marine ecosystems. 2. Setting the scene. ICES Journal of Marine Science. 2010 May 1;67(4):692-716.

https://doi.org/10.1016/j.radmeas.2010.08.003

Moon MJ. The evolution of e‐government among municipalities: rhetoric or reality?. Public administration review. 2002;62(4):424-33.

https://doi.org/10.1111/0033-3352.00196

Kim Y, Rush AM. Sequence-level knowledge distillation. arXiv preprint arXiv:1606.07947. 2016 Jun 25. https://doi.org/10.48550/arXiv.1606.07947

Nandini D, Manonmoney J, Lavanya J, Leela KV. Sujith. A Study on Prevalence and Characterization of Candida Species in Immunocompromised Patients. J Pure Appl Microbiol. 2021;15(4):2065-72.

https://doi.org/10.22207/JPAM.15.4.29

Nawal P, Patel S, Patel M, Soni S, Khandelwal N. A study of superficial mycoses in tertiary care hospital. J Age. 2012;6:11.

Yoon HJ, Choi HY, Kim YK, Song YJ, Ki M. Prevalence of fungal infections using National Health Insurance data from 2009-2013, South Korea. Epidemiology and health. 2014;36.

https://doi.org/10.4178%2Fepih%2Fe2014017

Cai W, Lu C, Li X, Zhang J, Zhan P, Xi L, et al. Epidemiology of superficial fungal infections in Guangdong, southern China: a retrospective study from 2004 to 2014. Mycopathologia. 2016 Jun;181:387-95. https://doi.10.1007/s11046-016-9986-6

Khodadadi H, Zomorodian K, Nouraei H, Zareshahrabadi Z, Barzegar S, Zare MR, et al. Prevalence of superficial‐cutaneous fungal infections in Shiraz, Iran: A five‐year retrospective study (2015–2019). Journal of Clinical Laboratory Analysis. 2021 Jul; 35(7):e23850.

https://doi.org/10.1002/jcla.23850

Palese B, Usai A. The relative importance of service quality dimensions in E-commerce experiences. International Journal of Information Management. 2018 Jun 1;40:132-40.

https://doi.org/10.1016/j.ijinfomgt.2018.02.001

Nam M, Kim SH, Jeong JH, Kim S, Kim J. Roles of the pro-apoptotic factors Canma111 and Caybh3 in apoptosis and virulence Of Candida Albicans. Scientific Reports. 2022 May 9;12(1):7574.

https://doi.org/10.1038/s41598-022-11682-y

Jayalakshmi R, Oviya R, Premalatha K, Mehetre ST, Paramasivam M, Kannan R, et al. Production, stability and degradation of Trichoderma gliotoxin in growth medium, irrigation water and agricultural soil. Scientific Reports. 2021 Aug 16;11(1):16536.

https://doi.org/10.1038/s41598-021-95907-6

Shah DT, Larsen B. Clinical isolates of yeast produce a gliotoxin-like substance. Mycopathologia. 1991 Dec;116:203-8.

https://doi.org/10.1007/BF00436836

Washburn RG, Gallin JI, Bennett JE. Oxidative killing of Aspergillus fumigatus proceeds by parallel myeloperoxidase-dependent and-independent pathways. Infection and immunity. 1987 Sep;55(9):2088-92.

https://doi.org/10.1128/iai.55.9.2088-2092.1987

Reeves EP, Lu H, Jacobs HL, Messina CG, Bolsover S, Gabella G, Potma EO, Warley A, Roes J, Segal AW. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature. 2002 Mar 21;416(6878):291-7.

https://doi.org/10.1038/416291a

Müllbacher A, Eichner RD. Immunosuppression in vitro by a metabolite of a human pathogenic fungus. Proceedings of the National Academy of Sciences. 1984 Jun;81(12):3835-7.

https://doi.org/10.1073/pnas.81.12.3835

Kim YS, Park SJ. Gliotoxin from the marine fungus Aspergillus fumigatus induces apoptosis in HT1080 fibrosarcoma cells by downregulating NF-κB. Fisheries and Aquatic Sciences. 2016 Dec;19(1):1-6.

https://doi.org/10.1186/s41240-016-0036-6

Chen S, Hu Y, Zhang J, Zhang P. Anti inflammatory effect of salusin β knockdown on LPS activated alveolar macrophages via NF κB inhibition and HO 1 activation. Molecular Medicine Reports. 2021 Feb 1;23(2):1-.

https://doi.org/10.3892/mmr.2020.11766

Bladt TT, Frisvad JC, Knudsen PB, Larsen TO. Anticancer and antifungal compounds from Aspergillus, Penicillium and other filamentous fungi. Molecules. 2013 Sep 13;18(9):11338-76.

https://doi.org/10.3390/molecules180911338

Waring P, Khan T, Sjaarda A. Apoptosis induced by gliotoxin is preceded by phosphorylation of histone H3 and enhanced sensitivity of chromatin to nuclease digestion. Journal of Biological Chemistry. 1997 Jul 18;272(29):17929-36. https://doi.org/10.1074/jbc.272.29.17929

Dheeb BI, Mohammad FI, Hadi YA, Abdulhameed BA. Cytotoxic effect of aflatoxin B1, gliotoxin, fumonisin B1, and zearalenone mycotoxins on HepG2 cell line in vitro. Int. J. Adv. Res. 2013;1(8):355-63.

Tang W, Liu ZL, Mai XY, Qi X, Li DH, Gu QQ, et al. Identification of Gliotoxin isolated from marine fungus as a new pyruvate kinase M2 inhibitor. Biochemical and Biophysical Research Communications. 2020 Jul 30;528(3):594-600.

https://doi.org/10.1016/j.bbrc.2020.05.139

Waring P, Beaver J. Gliotoxin and related epipolythiodioxopiperazines. General Pharmacology: The Vascular System. 1996 Dec 1;27(8):1311-6.

https://doi.org/10.1016/S0306-3623(96)00083-3

Herfarth H, Rath HC, Hofmeister R, Rogler G, Brand K, Schölmerich J, et al. In vivo treatment with the fungal metabolite gliotoxin suppresses intestinal inflammation in dextran sulphate sodium [DSS]-induced colitis. Gastroenterology. 1998(114):A993.

http://dx.doi.org/10.1016%2FS00165085(98)84042-0

Braithwaite AW, Eichner RD, Waring P, Müllbacher A. The immunomodulating agent gliotoxin causes genomic DNA fragmentation. Molecular immunology. 1987 Jan 1;24(1):47-55.

https://doi.org/10.1016/0161-5890(87)90110-6