SIRT1 Promotes Host Protective Immunity against Toxoplasma gondii by Controlling the FoxO-Autophagy Axis via the AMPK and PI3K/AKT Signalling Pathways

Abstract

Sirtuin 1 (SIRT1) regulates cellular processes by deacetylating non-histone targets, including transcription factors and intracellular signalling mediators; thus, its abnormal activation is closely linked to the pathophysiology of several diseases. However, its function in <i>Toxoplasma gondii</i> infection is unclear. We found that SIRT1 contributes to autophagy activation via the AMP-activated protein kinase (AMPK) and PI3K/AKT signalling pathways, promoting anti-<i>Toxoplasma</i> responses. Myeloid-specific <i>Sirt1</i>^-/- mice exhibited an increased cyst burden in brain tissue compared to wild-type mice following infection with the avirulent ME49 strain. Consistently, the intracellular survival of <i>T. gondii</i> was markedly increased in <i>Sirt1</i>-deficient bone-marrow-derived macrophages (BMDMs). In contrast, the activation of SIRT1 by resveratrol resulted in not only the induction of autophagy but also a significantly increased anti-<i>Toxoplasma</i> effect. Notably, SIRT1 regulates the FoxO-autophagy axis in several human diseases. Importantly, the <i>T. gondii</i>-induced phosphorylation, acetylation, and cytosolic translocation of FoxO1 was enhanced in <i>Sirt1</i>-deficient BMDMs and the pharmacological inhibition of PI3K/AKT signalling reduced the cytosolic translocation of FoxO1 in BMDMs infected with <i>T. gondii</i>. Further, the CaMKK2-dependent AMPK signalling pathway is responsible for the effect of SIRT1 on the FoxO3a-autophagy axis and for its anti-<i>Toxoplasma</i> activity. Collectively, our findings reveal a previously unappreciated role for SIRT1 in <i>Toxoplasma</i> infection.