Echinocandin-Induced Microevolution of Candida parapsilosis Influences Virulence and Abiotic Stress Tolerance

Csaba Papp, Katica Kocsis, Renáta Tóth, László Bodai, Jesse R. Willis, Ewa Ksiezopolska, Nancy E. Lozoya-Pérez, Csaba Vágvölgyi, Hector Mora Montes, Toni Gabaldón, Joshua D. Nosanchuk, Attila Gácser

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Candida species are a major cause of life-threatening bloodstream infections worldwide. Although Candida albicans is responsible for the vast majority of infections, the clinical relevance of other Candida species has also emerged over the last twenty years. This shift might be due in part to changes in clinical guidelines, as echinocandins became the first line of therapeutics for the treatment. Candida parapsilosis is an emerging non-albicans Candida species that exhibits lower susceptibility levels to these drugs. Candida species frequently display resistance to echinocandins, and the mechanism for this is well-known in C. albicans and Candida glabrata, where it is mediated by amino acid substitutions at defined locations of the β-1,3-glucan synthase, Fks1p. In C. parapsilosis isolates, Fks1p harbors an intrinsic amino acid change at position 660 of the hot spot 1 (HS1) region, which is thought to be responsible for the high MIC values. Less is known about acquired substitutions in this species. In this study, we used directed evolution experiments to generate C. parapsilosis strains with acquired resistance to caspofungin, anidulafungin, and micafungin. We showed that cross-resistance was dependent on the type of echinocandin used to generate the evolved strains. During their characterization, all mutant strains showed attenuated virulence in vivo and also displayed alterations in the exposure of inner cell wall components. The evolved strains harbored 251 amino acid changes, including three in the HS1, HS2, and HS3 regions of Fks1p. Altogether, our results demonstrate a direct connection between acquired antifungal resistance and virulence of C. parapsilosisIMPORTANCECandida parapsilosis is an opportunistic fungal pathogen with the ability to cause infections in immunocompromised patients. Echinocandins are the currently recommended first line of treatment for all Candida species. Resistance of Candida albicans to this drug type is well characterized. C. parapsilosis strains have the lowest in vitro susceptibility to echinocandins; however, patients with such infections typically respond well to echinocandin therapy. There is little knowledge of acquired resistance in C. parapsilosis and its consequences on other characteristics such as virulence properties. In this study, we aimed to dissect how acquired echinocandin resistance influences the pathogenicity of C. parapsilosis and to develop explanations for why echinocandins are clinically effective in the setting of acquired resistance.

Original languageEnglish (US)
JournalmSphere
Volume3
Issue number6
DOIs
StatePublished - Nov 14 2018

Fingerprint

Echinocandins
Candida
Virulence
Candida albicans
Infection
caspofungin
anidulafungin
Candida glabrata
Amino Acids
Immunocompromised Host
Amino Acid Substitution
Cellular Structures
Pharmaceutical Preparations
Cell Wall
Therapeutics
Guidelines

Keywords

  • Candida parapsilosis
  • echinocandins
  • microevolution
  • virulence

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

Cite this

Papp, C., Kocsis, K., Tóth, R., Bodai, L., Willis, J. R., Ksiezopolska, E., ... Gácser, A. (2018). Echinocandin-Induced Microevolution of Candida parapsilosis Influences Virulence and Abiotic Stress Tolerance. mSphere, 3(6). https://doi.org/10.1128/mSphere.00547-18

Echinocandin-Induced Microevolution of Candida parapsilosis Influences Virulence and Abiotic Stress Tolerance. / Papp, Csaba; Kocsis, Katica; Tóth, Renáta; Bodai, László; Willis, Jesse R.; Ksiezopolska, Ewa; Lozoya-Pérez, Nancy E.; Vágvölgyi, Csaba; Mora Montes, Hector; Gabaldón, Toni; Nosanchuk, Joshua D.; Gácser, Attila.

In: mSphere, Vol. 3, No. 6, 14.11.2018.

Research output: Contribution to journalArticle

Papp, C, Kocsis, K, Tóth, R, Bodai, L, Willis, JR, Ksiezopolska, E, Lozoya-Pérez, NE, Vágvölgyi, C, Mora Montes, H, Gabaldón, T, Nosanchuk, JD & Gácser, A 2018, 'Echinocandin-Induced Microevolution of Candida parapsilosis Influences Virulence and Abiotic Stress Tolerance', mSphere, vol. 3, no. 6. https://doi.org/10.1128/mSphere.00547-18
Papp, Csaba ; Kocsis, Katica ; Tóth, Renáta ; Bodai, László ; Willis, Jesse R. ; Ksiezopolska, Ewa ; Lozoya-Pérez, Nancy E. ; Vágvölgyi, Csaba ; Mora Montes, Hector ; Gabaldón, Toni ; Nosanchuk, Joshua D. ; Gácser, Attila. / Echinocandin-Induced Microevolution of Candida parapsilosis Influences Virulence and Abiotic Stress Tolerance. In: mSphere. 2018 ; Vol. 3, No. 6.
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abstract = "Candida species are a major cause of life-threatening bloodstream infections worldwide. Although Candida albicans is responsible for the vast majority of infections, the clinical relevance of other Candida species has also emerged over the last twenty years. This shift might be due in part to changes in clinical guidelines, as echinocandins became the first line of therapeutics for the treatment. Candida parapsilosis is an emerging non-albicans Candida species that exhibits lower susceptibility levels to these drugs. Candida species frequently display resistance to echinocandins, and the mechanism for this is well-known in C. albicans and Candida glabrata, where it is mediated by amino acid substitutions at defined locations of the β-1,3-glucan synthase, Fks1p. In C. parapsilosis isolates, Fks1p harbors an intrinsic amino acid change at position 660 of the hot spot 1 (HS1) region, which is thought to be responsible for the high MIC values. Less is known about acquired substitutions in this species. In this study, we used directed evolution experiments to generate C. parapsilosis strains with acquired resistance to caspofungin, anidulafungin, and micafungin. We showed that cross-resistance was dependent on the type of echinocandin used to generate the evolved strains. During their characterization, all mutant strains showed attenuated virulence in vivo and also displayed alterations in the exposure of inner cell wall components. The evolved strains harbored 251 amino acid changes, including three in the HS1, HS2, and HS3 regions of Fks1p. Altogether, our results demonstrate a direct connection between acquired antifungal resistance and virulence of C. parapsilosisIMPORTANCECandida parapsilosis is an opportunistic fungal pathogen with the ability to cause infections in immunocompromised patients. Echinocandins are the currently recommended first line of treatment for all Candida species. Resistance of Candida albicans to this drug type is well characterized. C. parapsilosis strains have the lowest in vitro susceptibility to echinocandins; however, patients with such infections typically respond well to echinocandin therapy. There is little knowledge of acquired resistance in C. parapsilosis and its consequences on other characteristics such as virulence properties. In this study, we aimed to dissect how acquired echinocandin resistance influences the pathogenicity of C. parapsilosis and to develop explanations for why echinocandins are clinically effective in the setting of acquired resistance.",
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AU - Bodai, László

AU - Willis, Jesse R.

AU - Ksiezopolska, Ewa

AU - Lozoya-Pérez, Nancy E.

AU - Vágvölgyi, Csaba

AU - Mora Montes, Hector

AU - Gabaldón, Toni

AU - Nosanchuk, Joshua D.

AU - Gácser, Attila

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