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 a...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Andrew S Wagner, Trevor J Hancock, Stephen W Lumsdaine, Sarah J Kauffman, Mikayla M Mangrum, Elise K Phillips, Timothy E Sparer, Todd B Reynolds
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/cdfab09a60b748168be22f81e6fb3981
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:cdfab09a60b748168be22f81e6fb3981
record_format	dspace
spelling	oai:doaj.org-article:cdfab09a60b748168be22f81e6fb39812021-12-02T20:00:15ZActivation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner.1553-73661553-737410.1371/journal.ppat.1009839https://doaj.org/article/cdfab09a60b748168be22f81e6fb39812021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009839https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Masking 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 (STE11ΔN467) 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 STE11ΔN467 mutant was dependent on the host immune system. Suppression of the immune response by cyclophosphamide reduced the attenuation in fungal burden caused by the STE11ΔN467 allele. Moreover, specific depletion of neutrophils via 1A8 antibody treatment also reduced STE11ΔN467-dependent fungal burden attenuation, but to a lesser extent than cyclophosphamide, demonstrating an important role for neutrophils in mediating fungal clearance of unmasked STE11ΔN467 cells. In an effort to understand the mechanism by which Ste11ΔN467 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 STE11ΔN467 strain, confirming that Cph1 is the transcription factor mediating Ste11ΔN467-induced unmasking. Furthermore, Cph1 is shown to induce a positive feedback loop that increases Cek1 activation. In addition, full unmasking by STE11ΔN467 is dependent on the upstream cell wall sensor DFI1. However, while deletion of DFI1 significantly reduced Ste11ΔN467-induced unmasking, it did not impact activation of the downstream kinase Cek1. Thus, it appears that once stimulated by Ste11ΔN467, Dfi1 activates a parallel signaling pathway that is involved in Ste11ΔN467-induced unmasking.Andrew S WagnerTrevor J HancockStephen W LumsdaineSarah J KauffmanMikayla M MangrumElise K PhillipsTimothy E SparerTodd B ReynoldsPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 8, p e1009839 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Andrew S Wagner Trevor J Hancock Stephen W Lumsdaine Sarah J Kauffman Mikayla M Mangrum Elise K Phillips Timothy E Sparer Todd B Reynolds Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner.
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 (STE11ΔN467) 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 STE11ΔN467 mutant was dependent on the host immune system. Suppression of the immune response by cyclophosphamide reduced the attenuation in fungal burden caused by the STE11ΔN467 allele. Moreover, specific depletion of neutrophils via 1A8 antibody treatment also reduced STE11ΔN467-dependent fungal burden attenuation, but to a lesser extent than cyclophosphamide, demonstrating an important role for neutrophils in mediating fungal clearance of unmasked STE11ΔN467 cells. In an effort to understand the mechanism by which Ste11ΔN467 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 STE11ΔN467 strain, confirming that Cph1 is the transcription factor mediating Ste11ΔN467-induced unmasking. Furthermore, Cph1 is shown to induce a positive feedback loop that increases Cek1 activation. In addition, full unmasking by STE11ΔN467 is dependent on the upstream cell wall sensor DFI1. However, while deletion of DFI1 significantly reduced Ste11ΔN467-induced unmasking, it did not impact activation of the downstream kinase Cek1. Thus, it appears that once stimulated by Ste11ΔN467, Dfi1 activates a parallel signaling pathway that is involved in Ste11ΔN467-induced unmasking.
format	article
author	Andrew S Wagner Trevor J Hancock Stephen W Lumsdaine Sarah J Kauffman Mikayla M Mangrum Elise K Phillips Timothy E Sparer Todd B Reynolds
author_facet	Andrew S Wagner Trevor J Hancock Stephen W Lumsdaine Sarah J Kauffman Mikayla M Mangrum Elise K Phillips Timothy E Sparer Todd B Reynolds
author_sort	Andrew S Wagner
title	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_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_sort	activation of cph1 causes ß(1,3)-glucan unmasking in candida albicans and attenuates virulence in mice in a neutrophil-dependent manner.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/cdfab09a60b748168be22f81e6fb3981
work_keys_str_mv	AT andrewswagner activationofcph1causesß13glucanunmaskingincandidaalbicansandattenuatesvirulenceinmiceinaneutrophildependentmanner AT trevorjhancock activationofcph1causesß13glucanunmaskingincandidaalbicansandattenuatesvirulenceinmiceinaneutrophildependentmanner AT stephenwlumsdaine activationofcph1causesß13glucanunmaskingincandidaalbicansandattenuatesvirulenceinmiceinaneutrophildependentmanner AT sarahjkauffman activationofcph1causesß13glucanunmaskingincandidaalbicansandattenuatesvirulenceinmiceinaneutrophildependentmanner AT mikaylammangrum activationofcph1causesß13glucanunmaskingincandidaalbicansandattenuatesvirulenceinmiceinaneutrophildependentmanner AT elisekphillips activationofcph1causesß13glucanunmaskingincandidaalbicansandattenuatesvirulenceinmiceinaneutrophildependentmanner AT timothyesparer activationofcph1causesß13glucanunmaskingincandidaalbicansandattenuatesvirulenceinmiceinaneutrophildependentmanner AT toddbreynolds activationofcph1causesß13glucanunmaskingincandidaalbicansandattenuatesvirulenceinmiceinaneutrophildependentmanner
_version_	1718375747937107968

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

Ejemplares similares