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Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner

Masking the immunogenic cell wall epitope ß(1,3)-glucan under an outer layer of mannosylated glycoproteins is an important virulence factor deployed by Candida albicans during infection. Consequently, increased ß(1,3)-glucan exposure (unmasking) reveals C. albicans to the host’s immune system and at...

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Autores principales: Wagner, Andrew S., Hancock, Trevor J., Lumsdaine, Stephen W., Kauffman, Sarah J., Mangrum, Mikayla M., Phillips, Elise K., Sparer, Timothy E., Reynolds, Todd B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423308/
https://www.ncbi.nlm.nih.gov/pubmed/34432857
http://dx.doi.org/10.1371/journal.ppat.1009839
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author Wagner, Andrew S.
Hancock, Trevor J.
Lumsdaine, Stephen W.
Kauffman, Sarah J.
Mangrum, Mikayla M.
Phillips, Elise K.
Sparer, Timothy E.
Reynolds, Todd B.
author_facet Wagner, Andrew S.
Hancock, Trevor J.
Lumsdaine, Stephen W.
Kauffman, Sarah J.
Mangrum, Mikayla M.
Phillips, Elise K.
Sparer, Timothy E.
Reynolds, Todd B.
author_sort Wagner, Andrew S.
collection PubMed
description Masking the immunogenic cell wall epitope ß(1,3)-glucan under an outer layer of mannosylated glycoproteins is an important virulence factor deployed by Candida albicans during infection. Consequently, increased ß(1,3)-glucan exposure (unmasking) reveals C. albicans to the host’s immune system and attenuates its virulence. We have previously shown that activation of the Cek1 MAPK pathway via expression of a hyperactive allele of an upstream kinase (STE11(ΔN467)) induced unmasking. It also increased survival of mice in a murine disseminated candidiasis model and attenuated kidney fungal burden by ≥33 fold. In this communication, we utilized cyclophosphamide-induced immunosuppression to test if the clearance of the unmasked STE11(ΔN467) mutant was dependent on the host immune system. Suppression of the immune response by cyclophosphamide reduced the attenuation in fungal burden caused by the STE11(ΔN467) allele. Moreover, specific depletion of neutrophils via 1A8 antibody treatment also reduced STE11(ΔN467)-dependent fungal burden attenuation, but to a lesser extent than cyclophosphamide, demonstrating an important role for neutrophils in mediating fungal clearance of unmasked STE11(ΔN467) cells. In an effort to understand the mechanism by which Ste11(ΔN467) causes unmasking, transcriptomics were used to reveal that several components in the Cek1 MAPK pathway were upregulated, including the transcription factor CPH1 and the cell wall sensor DFI1. In this report we show that a cph1ΔΔ mutation restored ß(1,3)-glucan exposure to wild-type levels in the STE11(ΔN467) strain, confirming that Cph1 is the transcription factor mediating Ste11(ΔN467)-induced unmasking. Furthermore, Cph1 is shown to induce a positive feedback loop that increases Cek1 activation. In addition, full unmasking by STE11(ΔN467) is dependent on the upstream cell wall sensor DFI1. However, while deletion of DFI1 significantly reduced Ste11(ΔN467)-induced unmasking, it did not impact activation of the downstream kinase Cek1. Thus, it appears that once stimulated by Ste11(ΔN467), Dfi1 activates a parallel signaling pathway that is involved in Ste11(ΔN467)-induced unmasking.
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spelling pubmed-84233082021-09-08 Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner Wagner, Andrew S. Hancock, Trevor J. Lumsdaine, Stephen W. Kauffman, Sarah J. Mangrum, Mikayla M. Phillips, Elise K. Sparer, Timothy E. Reynolds, Todd B. PLoS Pathog Research Article Masking the immunogenic cell wall epitope ß(1,3)-glucan under an outer layer of mannosylated glycoproteins is an important virulence factor deployed by Candida albicans during infection. Consequently, increased ß(1,3)-glucan exposure (unmasking) reveals C. albicans to the host’s immune system and attenuates its virulence. We have previously shown that activation of the Cek1 MAPK pathway via expression of a hyperactive allele of an upstream kinase (STE11(ΔN467)) induced unmasking. It also increased survival of mice in a murine disseminated candidiasis model and attenuated kidney fungal burden by ≥33 fold. In this communication, we utilized cyclophosphamide-induced immunosuppression to test if the clearance of the unmasked STE11(ΔN467) mutant was dependent on the host immune system. Suppression of the immune response by cyclophosphamide reduced the attenuation in fungal burden caused by the STE11(ΔN467) allele. Moreover, specific depletion of neutrophils via 1A8 antibody treatment also reduced STE11(ΔN467)-dependent fungal burden attenuation, but to a lesser extent than cyclophosphamide, demonstrating an important role for neutrophils in mediating fungal clearance of unmasked STE11(ΔN467) cells. In an effort to understand the mechanism by which Ste11(ΔN467) causes unmasking, transcriptomics were used to reveal that several components in the Cek1 MAPK pathway were upregulated, including the transcription factor CPH1 and the cell wall sensor DFI1. In this report we show that a cph1ΔΔ mutation restored ß(1,3)-glucan exposure to wild-type levels in the STE11(ΔN467) strain, confirming that Cph1 is the transcription factor mediating Ste11(ΔN467)-induced unmasking. Furthermore, Cph1 is shown to induce a positive feedback loop that increases Cek1 activation. In addition, full unmasking by STE11(ΔN467) is dependent on the upstream cell wall sensor DFI1. However, while deletion of DFI1 significantly reduced Ste11(ΔN467)-induced unmasking, it did not impact activation of the downstream kinase Cek1. Thus, it appears that once stimulated by Ste11(ΔN467), Dfi1 activates a parallel signaling pathway that is involved in Ste11(ΔN467)-induced unmasking. Public Library of Science 2021-08-25 /pmc/articles/PMC8423308/ /pubmed/34432857 http://dx.doi.org/10.1371/journal.ppat.1009839 Text en © 2021 Wagner et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wagner, Andrew S.
Hancock, Trevor J.
Lumsdaine, Stephen W.
Kauffman, Sarah J.
Mangrum, Mikayla M.
Phillips, Elise K.
Sparer, Timothy E.
Reynolds, Todd B.
Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner
title Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner
title_full Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner
title_fullStr Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner
title_full_unstemmed Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner
title_short Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner
title_sort activation of cph1 causes ß(1,3)-glucan unmasking in candida albicans and attenuates virulence in mice in a neutrophil-dependent manner
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423308/
https://www.ncbi.nlm.nih.gov/pubmed/34432857
http://dx.doi.org/10.1371/journal.ppat.1009839
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