Myeloid cell deficiency of p38 gamma/p38 delta 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 p38 gamma and p38 delta regulate the...

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Detalles Bibliográficos
Autores: Alsina-Beauchamp, Dayanira, Escos, Alejandra, Fajardo, Pilar, Gonzalez-Romero, Diego, Diaz-Mora, Ester, Risco, Ana, Martin-Serrano, Miguel A., del Fresno, Carlos, Domínguez-Andrés, Jorge, Aparicio, Noelia, Zur, Rafal, Shpiro, Natalia, Brown, Gordon D., Ardavín, Carlos, Netea, Mihai G, Alemany, Susana, Sanz-Ezquerro, Juan J., Cuenda, Ana
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/6673
Acceso en línea:http://hdl.handle.net/20.500.12105/6673
Access Level:acceso abierto
Palabra clave:Candida albicans
Infection
Kinase inhibitor
p38MAPK
Signalling
PATTERN-RECOGNITION RECEPTORS
TNF-ALPHA PRODUCTION
LOCI-2 TPL2 KINASE
INNATE IMMUNITY
IN-VIVO
INVASIVE CANDIDIASIS
CROSS-TALK
INFLAMMATION
P38-GAMMA
P38-DELTA
Descripción
Sumario: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 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.

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