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dc.contributor.authorAlsina-Beauchamp, Dayanira
dc.contributor.authorEscos, Alejandra
dc.contributor.authorFajardo, Pilar
dc.contributor.authorGonzalez-Romero, Diego
dc.contributor.authorDiaz-Mora, Ester
dc.contributor.authorRisco, Ana
dc.contributor.authorMartin-Serrano, Miguel A.
dc.contributor.authordel Fresno, Carlos 
dc.contributor.authorDominguez-Andres, Jorge
dc.contributor.authorAparicio, Noelia
dc.contributor.authorZur, Rafal
dc.contributor.authorShpiro, Natalia
dc.contributor.authorBrown, Gordon D.
dc.contributor.authorArdavín, Carlos
dc.contributor.authorNetea, Mihai G
dc.contributor.authorAlemany, Susana
dc.contributor.authorSanz-Ezquerro, Juan J.
dc.contributor.authorCuenda, Ana
dc.date.accessioned2018-11-22T08:10:51Z
dc.date.available2018-11-22T08:10:51Z
dc.date.issued2018
dc.identifierISI:000431632400002
dc.identifier.citationEMBO Mol Med. 2018; 10(5):e8485
dc.identifier.issn1757-4676
dc.identifier.urihttp://hdl.handle.net/20.500.12105/6673
dc.description.abstractCandida 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 p38 gamma and p38 delta 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 p38 gamma/p38 delta. In mice, p38 gamma/p38 delta 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 p38 beta/delta-null mice, reducing septic shock. p38 gamma/p38 delta in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38 gamma/p38 delta in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.
dc.description.sponsorshipWe thank P. Cohen for critically reading the manuscript. 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 Marato 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.
dc.language.isoeng
dc.publisherWiley 
dc.type.hasVersionVoR
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectCandida albicans
dc.subjectInfection
dc.subjectKinase inhibitor
dc.subjectp38MAPK
dc.subjectSignalling
dc.subjectPATTERN-RECOGNITION RECEPTORS
dc.subjectTNF-ALPHA PRODUCTION
dc.subjectLOCI-2 TPL2 KINASE
dc.subjectINNATE IMMUNITY
dc.subjectIN-VIVO
dc.subjectINVASIVE CANDIDIASIS
dc.subjectCROSS-TALK
dc.subjectINFLAMMATION
dc.subjectP38-GAMMA
dc.subjectP38-DELTA
dc.titleMyeloid cell deficiency of p38 gamma/p38 delta protects against candidiasis and regulates antifungal immunity
dc.typejournal article
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID29661910
dc.format.volume10
dc.identifier.doi10.15252/emmm.201708485
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderFundación La Marató TV3 
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC) 
dc.contributor.funderDutch Research Council (Holanda) 
dc.contributor.funderWellcome Trust 
dc.contributor.funderMedical Research Council (Reino Unido) 
dc.identifier.e-issn1757-4684
dc.relation.publisherversionhttps://doi.org/10.15252/emmm.201708485
dc.identifier.journalEMBO Molecular Medicine
dc.repisalud.orgCNICCNIC::Grupos de investigación::Inmunobiología
dc.repisalud.institucionCNIC
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2013-45331-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2016-79792-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/310372es_ES
dc.rights.accessRightsopen accesses_ES


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Atribución 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Atribución 4.0 Internacional