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EMBO Mol Med. 2018 May;10(5). pii: e8485. doi: 10.15252/emmm.201708485.

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

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Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
Immunobiology of Inflammation Laboratory Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
Medical Research Council Protein Phosphorylation Unit, Sir James Black Building, School of Life Sciences, University of Dundee, Dundee, UK.
Aberdeen Fungal Group, Institute of Medical Sciences, Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen, UK.
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.
Department of Cellular and Molecular Biology, CNB/CSIC, Madrid, Spain.
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain


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.


Candida albicans ; infection; kinase inhibitor; p38MAPK; signalling

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