Abstract
Candida albicans is a frequent etiologic 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 p38J and p38G 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 p38J/p38G. In mice, p38J/p38G 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 p38J/G null mice, reducing septic shock. p38J/p38G in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38J/p38G in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.
Original language | English |
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Article number | e8485 |
Journal | EMBO Molecular Medicine |
Volume | 10 |
Issue number | 5 |
Early online date | 16 Apr 2018 |
DOIs | |
Publication status | Published - May 2018 |
Bibliographical note
Fundació la Marató de TV3 (GrantNumber(s): 20133431; Grant recipient(s): Ana Cuenda)Wellcome Trust (GrantNumber(s): 97377, 102705; Grant recipient(s): GORDON D. BROWN)
Ministerio de Economía y Competitividad (GrantNumber(s): SAF2016-79792-R, SAF2014- 52009-R, SAF2013-45331-R; Grant recipient(s): Ana Cuenda, SUSANA ALEMANY)
Medical Research Council (GrantNumber(s): MR/N006364/1; Grant recipient(s): GORDON D. BROWN)
ERC Consolidator Grant (GrantNumber(s): 310372; Grant recipient(s): Mihai Netea)
Keywords
- p38MAPK
- signalling
- infection
- Candida albicans
- Kinase inhibitor