Akt-1 and Akt-2 are the major isoforms of the serine/threonine Akt family that play a key role in controlling immune responses. However, the involvement of Akt-1 and Akt-2 isoforms in antifungal innate immunity is completely unknown. In this study, we show that Akt2−/−, but not Akt1−/−, mice are protected from lethal Candida albicans infection. Loss of Akt-2 facilitates the recruitment of neutrophils and macrophages to the spleen and increases reactive oxygen species expression in these cells. Treating C57BL/6 mice with a specific inhibitor for Akt-2, but not Akt-1, provides protection from lethal C. albicans infection. Our data demonstrate that Akt-2 inhibits antifungal innate immunity by hampering neutrophil and macrophage recruitment to spleens and suppressing oxidative burst, myeloperoxidase activity, and NETosis. We thus describe a novel role for Akt-2 in the regulation of antifungal innate immunity and unveil Akt-2 as a potential target for the treatment of fungal sepsis.

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