Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity

Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate imm...

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Authors: Alsina-Beauchamp, Dayanira, Escós, Alejandra, Fajardo, Alicia, González‐Romero, Diego, Díaz-Mora, Ester, Risco, Ana, Martín‐Serrano, Miguel A., Fresno, Carlos del, Dominguez‐Andrés, Jorge, Aparicio, Noelia, Zur, Rafal, Shpiro, Natalia, Brown, Gordon D., Ardavín, Carlos, Netea, Mihai G., Alemany, Susana, Sanz-Ezquerro, Juan José, Cuenda, Ana
Format: article
Status:Published version
Publication Date:2018
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/188301
Online Access:http://hdl.handle.net/10261/188301
Access Level:Open access
Keyword:Candida albicans
Infection
Kinase inhibitor
p38MAPK
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spelling Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunityAlsina-Beauchamp, DayaniraEscós, AlejandraFajardo, AliciaGonzález‐Romero, DiegoDíaz-Mora, EsterRisco, AnaMartín‐Serrano, Miguel A.Fresno, Carlos delDominguez‐Andrés, JorgeAparicio, NoeliaZur, RafalShpiro, NataliaBrown, Gordon D.Ardavín, CarlosNetea, Mihai G.Alemany, SusanaSanz-Ezquerro, Juan JoséCuenda, AnaCandida albicansInfectionKinase inhibitorp38MAPKCandida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans. We describe a new TAK1‐TPL2‐MKK1‐ERK1/2 pathway in macrophages, which is activated by Dectin‐1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper‐inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38γ/δ‐null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.This work was supported by grants from the MINECO [SAF2013‐45331‐R and SAF2016‐79792‐R (AEI/FEDER, UE)] to AC and JJS‐E, La Marató TV3 Foundation (20133431) to AC and (SAF2014‐52009‐R) to SA. ERC Consolidator Grant (#310372) and a Spinoza grant of the Netherlands Organization for Scientific Research to MGN, and Wellcome Trust, the Medical Research Council (MRC; UK), the MRC Centre for Medical Mycology at the University of Aberdeen to GDB. DAB and AE receive MINECO FPI fellowships, AR a MINECO Juan de la Cierva award and JD‐A a La Caixa Foundation PhD fellowship.Peer reviewedEuropean Molecular Biology OrganizationWiley-VCHFundació La Marató de TV3European Research CouncilMinisterio de Economía y Competitividad (España)Netherlands Organization for Scientific ResearchWellcome TrustMedical Research Council (UK)University of AberdeenFundación la CaixaEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/188301reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2013‐45331‐Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016‐79792‐Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014‐52009‐Rinfo:eu-repo/grantAgreement/EC/FP7/310372https://doi.org/10.15252/emmm.201708485Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1883012026-05-22T06:33:51Z
dc.title.none.fl_str_mv Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
title Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
spellingShingle Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
Alsina-Beauchamp, Dayanira
Candida albicans
Infection
Kinase inhibitor
p38MAPK
title_short Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
title_full Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
title_fullStr Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
title_full_unstemmed Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
title_sort Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
dc.creator.none.fl_str_mv Alsina-Beauchamp, Dayanira
Escós, Alejandra
Fajardo, Alicia
González‐Romero, Diego
Díaz-Mora, Ester
Risco, Ana
Martín‐Serrano, Miguel A.
Fresno, Carlos del
Dominguez‐Andrés, Jorge
Aparicio, Noelia
Zur, Rafal
Shpiro, Natalia
Brown, Gordon D.
Ardavín, Carlos
Netea, Mihai G.
Alemany, Susana
Sanz-Ezquerro, Juan José
Cuenda, Ana
author Alsina-Beauchamp, Dayanira
author_facet Alsina-Beauchamp, Dayanira
Escós, Alejandra
Fajardo, Alicia
González‐Romero, Diego
Díaz-Mora, Ester
Risco, Ana
Martín‐Serrano, Miguel A.
Fresno, Carlos del
Dominguez‐Andrés, Jorge
Aparicio, Noelia
Zur, Rafal
Shpiro, Natalia
Brown, Gordon D.
Ardavín, Carlos
Netea, Mihai G.
Alemany, Susana
Sanz-Ezquerro, Juan José
Cuenda, Ana
author_role author
author2 Escós, Alejandra
Fajardo, Alicia
González‐Romero, Diego
Díaz-Mora, Ester
Risco, Ana
Martín‐Serrano, Miguel A.
Fresno, Carlos del
Dominguez‐Andrés, Jorge
Aparicio, Noelia
Zur, Rafal
Shpiro, Natalia
Brown, Gordon D.
Ardavín, Carlos
Netea, Mihai G.
Alemany, Susana
Sanz-Ezquerro, Juan José
Cuenda, Ana
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundació La Marató de TV3
European Research Council
Ministerio de Economía y Competitividad (España)
Netherlands Organization for Scientific Research
Wellcome Trust
Medical Research Council (UK)
University of Aberdeen
Fundación la Caixa
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Candida albicans
Infection
Kinase inhibitor
p38MAPK
topic Candida albicans
Infection
Kinase inhibitor
p38MAPK
description Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans. We describe a new TAK1‐TPL2‐MKK1‐ERK1/2 pathway in macrophages, which is activated by Dectin‐1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper‐inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38γ/δ‐null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/188301
url http://hdl.handle.net/10261/188301
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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#PLACEHOLDER_PARENT_METADATA_VALUE#
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info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2013‐45331‐R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016‐79792‐R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014‐52009‐R
info:eu-repo/grantAgreement/EC/FP7/310372
https://doi.org/10.15252/emmm.201708485
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv European Molecular Biology Organization
Wiley-VCH
publisher.none.fl_str_mv European Molecular Biology Organization
Wiley-VCH
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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