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Myeloid cell deficiency of p38?/p38? protects against candidiasis and regulates antifungal immunity.


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 p38? and p38? 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 p38?/p38?. In mice, p38?/p38? 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 p38?/?-null mice, reducing septic shock. p38?/p38? in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38?/p38? in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.

SUBMITTER: Alsina-Beauchamp D 

PROVIDER: S-EPMC5938613 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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<i>Candida albicans</i> 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 <i>C. albicans</i> 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  ...[more]

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