Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.

Candida albicans is a major human pathogen whose treatment is challenging due to antifungal drug toxicity, drug resistance and paucity of antifungal agents available. Myrocin (MYR) inhibits sphingosine synthesis, a precursor of sphingolipids, an important cell membrane and signaling molecule compone...

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Autores principales:	Nadja Rodrigues de Melo, Ahmed Abdrahman, Carolyn Greig, Krishnendu Mukherjee, Catherine Thornton, Norman A Ratcliffe, Andreas Vilcinskas, Tariq M Butt
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6d66e5047bb547e09bedfbf2992af3a7
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spelling	oai:doaj.org-article:6d66e5047bb547e09bedfbf2992af3a72021-11-18T08:46:09ZMyriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.1932-620310.1371/journal.pone.0078905https://doaj.org/article/6d66e5047bb547e09bedfbf2992af3a72013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24260135/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Candida albicans is a major human pathogen whose treatment is challenging due to antifungal drug toxicity, drug resistance and paucity of antifungal agents available. Myrocin (MYR) inhibits sphingosine synthesis, a precursor of sphingolipids, an important cell membrane and signaling molecule component. MYR also has dual immune suppressive and antifungal properties, potentially modulating mammalian immunity and simultaneously reducing fungal infection risk. Wax moth (Galleria mellonella) larvae, alternatives to mice, were used to establish if MYR suppressed insect immunity and increased survival of C. albicans-infected insects. MYR effects were studied in vivo and in vitro, and compared alone and combined with those of approved antifungal drugs, fluconazole (FLC) and amphotericin B (AMPH). Insect immune defenses failed to inhibit C. albicans with high mortalities. In insects pretreated with the drug followed by C. albicans inoculation, MYR+C. albicans significantly increased mortality to 93% from 67% with C. albicans alone 48 h post-infection whilst AMPH+C. albicans and FLC+C. albicans only showed 26% and 0% mortalities, respectively. MYR combinations with other antifungal drugs in vivo also enhanced larval mortalities, contrasting the synergistic antifungal effect of the MYR+AMPH combination in vitro. MYR treatment influenced immunity and stress management gene expression during C. albicans pathogenesis, modulating transcripts putatively associated with signal transduction/regulation of cytokines, I-kappaB kinase/NF-kappaB cascade, G-protein coupled receptor and inflammation. In contrast, all stress management gene expression was down-regulated in FLC and AMPH pretreated C. albicans-infected insects. Results are discussed with their implications for clinical use of MYR to treat sphingolipid-associated disorders.Nadja Rodrigues de MeloAhmed AbdrahmanCarolyn GreigKrishnendu MukherjeeCatherine ThorntonNorman A RatcliffeAndreas VilcinskasTariq M ButtPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e78905 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nadja Rodrigues de Melo Ahmed Abdrahman Carolyn Greig Krishnendu Mukherjee Catherine Thornton Norman A Ratcliffe Andreas Vilcinskas Tariq M Butt Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.
description	Candida albicans is a major human pathogen whose treatment is challenging due to antifungal drug toxicity, drug resistance and paucity of antifungal agents available. Myrocin (MYR) inhibits sphingosine synthesis, a precursor of sphingolipids, an important cell membrane and signaling molecule component. MYR also has dual immune suppressive and antifungal properties, potentially modulating mammalian immunity and simultaneously reducing fungal infection risk. Wax moth (Galleria mellonella) larvae, alternatives to mice, were used to establish if MYR suppressed insect immunity and increased survival of C. albicans-infected insects. MYR effects were studied in vivo and in vitro, and compared alone and combined with those of approved antifungal drugs, fluconazole (FLC) and amphotericin B (AMPH). Insect immune defenses failed to inhibit C. albicans with high mortalities. In insects pretreated with the drug followed by C. albicans inoculation, MYR+C. albicans significantly increased mortality to 93% from 67% with C. albicans alone 48 h post-infection whilst AMPH+C. albicans and FLC+C. albicans only showed 26% and 0% mortalities, respectively. MYR combinations with other antifungal drugs in vivo also enhanced larval mortalities, contrasting the synergistic antifungal effect of the MYR+AMPH combination in vitro. MYR treatment influenced immunity and stress management gene expression during C. albicans pathogenesis, modulating transcripts putatively associated with signal transduction/regulation of cytokines, I-kappaB kinase/NF-kappaB cascade, G-protein coupled receptor and inflammation. In contrast, all stress management gene expression was down-regulated in FLC and AMPH pretreated C. albicans-infected insects. Results are discussed with their implications for clinical use of MYR to treat sphingolipid-associated disorders.
format	article
author	Nadja Rodrigues de Melo Ahmed Abdrahman Carolyn Greig Krishnendu Mukherjee Catherine Thornton Norman A Ratcliffe Andreas Vilcinskas Tariq M Butt
author_facet	Nadja Rodrigues de Melo Ahmed Abdrahman Carolyn Greig Krishnendu Mukherjee Catherine Thornton Norman A Ratcliffe Andreas Vilcinskas Tariq M Butt
author_sort	Nadja Rodrigues de Melo
title	Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.
title_short	Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.
title_full	Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.
title_fullStr	Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.
title_full_unstemmed	Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.
title_sort	myriocin significantly increases the mortality of a non-mammalian model host during candida pathogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/6d66e5047bb547e09bedfbf2992af3a7
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Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.

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