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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.

Author information

1
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
2
Immunobiology of Inflammation Laboratory Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
3
Medical Research Council Protein Phosphorylation Unit, Sir James Black Building, School of Life Sciences, University of Dundee, Dundee, UK.
4
Aberdeen Fungal Group, Institute of Medical Sciences, Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen, UK.
5
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
6
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.
7
Department of Cellular and Molecular Biology, CNB/CSIC, Madrid, Spain.
8
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain acuenda@cnb.csic.es.

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.

KEYWORDS:

Candida albicans ; infection; kinase inhibitor; p38MAPK; signalling

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