SIRT1 Promotes Host Protective Immunity against Toxoplasma gondii by Controlling the FoxO-Autophagy Axis via the AMPK
Jina Lee1,2,3, Jinju Kim1,2,3, Jae-Hyung Lee1,2,3
1Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea.
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 Toxoplasma gondii 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-Toxoplasma responses. Myeloid-specific Sirt1-/- 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 T. gondii was markedly increased in Sirt1-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-Toxoplasma effect. Notably, SIRT1 regulates the FoxO-autophagy axis in several human diseases. Importantly, the T. gondii-induced phosphorylation, acetylation, and cytosolic translocation of FoxO1 was enhanced in Sirt1-deficient BMDMs and the pharmacological inhibition of PI3K/AKT signalling reduced the cytosolic translocation of FoxO1 in BMDMs infected with T. gondii. Further, the CaMKK2-dependent AMPK signalling pathway is responsible for the effect of SIRT1 on the FoxO3a-autophagy axis and for its anti-Toxoplasma activity. Collectively, our findings reveal a previously unappreciated role for SIRT1 in Toxoplasma infection.
Insights
Sirtuin 1 (SIRT1) activates autophagy and enhances anti-Toxoplasma responses by regulating the FoxO-autophagy axis. SIRT1 deficiency increases parasite burden, highlighting its crucial role in controlling Toxoplasma gondii infection.
Area of Science:
- Cellular Biology
- Immunology
- Parasitology
Background:
- Sirtuin 1 (SIRT1) is a deacetylase involved in various cellular processes and disease pathophysiology.
- The role of SIRT1 in *Toxoplasma gondii* infection has not been previously elucidated.
Purpose of the Study:
- To investigate the function of SIRT1 in host responses during *Toxoplasma gondii* infection.
- To elucidate the molecular mechanisms by which SIRT1 influences anti-parasitic immunity.
Main Methods:
- Utilized myeloid-specific *Sirt1* knockout mice and *Sirt1*-deficient bone-marrow-derived macrophages (BMDMs).
- Assessed *Toxoplasma gondii* cyst burden and intracellular parasite survival.
- Investigated the involvement of AMP-activated protein kinase (AMPK), PI3K/AKT, and FoxO signalling pathways.
- Examined the effect of resveratrol, a SIRT1 activator.
Main Results:
- SIRT1 activation promotes autophagy via AMPK and PI3K/AKT pathways, enhancing anti-*Toxoplasma* responses.
- *Sirt1* deficiency in myeloid cells led to increased brain cyst burden and enhanced *T. gondii* survival in BMDMs.
- Resveratrol activation of SIRT1 induced autophagy and boosted anti-*Toxoplasma* effects.
- SIRT1 regulates the FoxO-autophagy axis, with *T. gondii* infection altering FoxO1 phosphorylation, acetylation, and translocation in *Sirt1*-deficient BMDMs.
Conclusions:
- SIRT1 plays a significant role in controlling *Toxoplasma gondii* infection by promoting autophagy and anti-parasitic immunity.
- The SIRT1-mediated regulation of the FoxO-autophagy axis is critical for host defense against *T. gondii*.
- Targeting SIRT1 may offer a therapeutic strategy against *Toxoplasma* infections.
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