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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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/188301
Acceso en línea:http://hdl.handle.net/10261/188301
Access Level:acceso abierto
Palabra clave:Candida albicans
Infection
Kinase inhibitor
p38MAPK
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 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.

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