PMID- 36362370 OWN - NLM STAT- MEDLINE DCOM- 20221121 LR - 20221121 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 21 DP - 2022 Nov 5 TI - SIRT1 Promotes Host Protective Immunity against Toxoplasma gondii by Controlling the FoxO-Autophagy Axis via the AMPK and PI3K/AKT Signalling Pathways. LID - 10.3390/ijms232113578 [doi] LID - 13578 AB - 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. FAU - Lee, Jina AU - Lee J AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea. FAU - Kim, Jinju AU - Kim J AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea. FAU - Lee, Jae-Hyung AU - Lee JH AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea. FAU - Choi, Yong Min AU - Choi YM AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea. FAU - Choi, Hyeonil AU - Choi H AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. FAU - Cho, Hwan-Doo AU - Cho HD AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. FAU - Cha, Guang-Ho AU - Cha GH AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea. FAU - Lee, Young-Ha AU - Lee YH AUID- ORCID: 0000-0002-5795-8960 AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea. FAU - Jo, Eun-Kyeong AU - Jo EK AD - Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. FAU - Park, Byung-Hyun AU - Park BH AUID- ORCID: 0000-0003-3768-4285 AD - Department of Biochemistry, Chonbuk National University Medical School, Jeonju 54896, Korea. FAU - Yuk, Jae-Min AU - Yuk JM AUID- ORCID: 0000-0002-0630-9194 AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea. LA - eng GR - 2019R1C1C1004431/National Research Foundation of Korea/ GR - 2017R1A5A2015385/National Research Foundation of Korea/ GR - 2022R1C1C1004346/National Research Foundation of Korea/ PT - Journal Article DEP - 20221105 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase) RN - EC 2.7.11.17 (CAMKK2 protein, human) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.5.1.- (SIRT1 protein, human) RN - EC 3.5.1.- (Sirt1 protein, mouse) RN - EC 3.5.1.- (Sirtuin 1) RN - 0 (Forkhead Transcription Factors) SB - IM MH - Animals MH - Humans MH - Mice MH - AMP-Activated Protein Kinases/metabolism MH - Autophagy MH - Calcium-Calmodulin-Dependent Protein Kinase Kinase MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Sirtuin 1/genetics MH - *Toxoplasma/metabolism MH - Forkhead Transcription Factors/metabolism PMC - PMC9654124 OTO - NOTNLM OT - AMP-activated protein kinase OT - Class O of forkhead box transcription factors OT - PI3K/AKT signalling pathway OT - Sirtuin 1 OT - Toxoplasma gondii OT - autophagy OT - bone-marrow-derived macrophages COIS- The authors declare no conflict of interest. EDAT- 2022/11/12 06:00 MHDA- 2022/11/15 06:00 PMCR- 2022/11/05 CRDT- 2022/11/11 01:29 PHST- 2022/08/24 00:00 [received] PHST- 2022/10/06 00:00 [revised] PHST- 2022/11/03 00:00 [accepted] PHST- 2022/11/11 01:29 [entrez] PHST- 2022/11/12 06:00 [pubmed] PHST- 2022/11/15 06:00 [medline] PHST- 2022/11/05 00:00 [pmc-release] AID - ijms232113578 [pii] AID - ijms-23-13578 [pii] AID - 10.3390/ijms232113578 [doi] PST - epublish SO - Int J Mol Sci. 2022 Nov 5;23(21):13578. doi: 10.3390/ijms232113578.