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

Dayanira Alsina-Beauchamp, Alejandra Escós, Pilar Fajardo, Diego González-Romero, Ester Díaz-Mora, Ana Risco, Miguel A. Martín-Serrano, Carlos Del Fresno, Jorge Dominguez-Andrés, Noelia Aparicio, Rafal Zur, Natalia Shpiro, Gordon D. Brown, Carlos Ardavín, Mihai G. Netea, Susana Alemany, Juan J. Sanz-Ezquerro, Ana Cuenda (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Article numbere8485
Pages (from-to)1-15
Number of pages15
JournalEmbo Molecular Medicine
Volume10
Issue number5
Early online date16 Apr 2018
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • Candida albicans
  • infection
  • kinase inhibitor
  • p38MAPK
  • signalling

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    Alsina-Beauchamp, D., Escós, A., Fajardo, P., González-Romero, D., Díaz-Mora, E., Risco, A., Martín-Serrano, M. A., Del Fresno, C., Dominguez-Andrés, J., Aparicio, N., Zur, R., Shpiro, N., Brown, G. D., Ardavín, C., Netea, M. G., Alemany, S., Sanz-Ezquerro, J. J., & Cuenda, A. (2018). Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. Embo Molecular Medicine, 10(5), 1-15. [e8485]. https://doi.org/10.15252/emmm.201708485