Histone deacetylase SIR2 in Toxoplasma gondii modulates functions of murine macrophages in vitro and protects mice against acute toxoplasmosis in vivo

ZhengQing Yu; SiYing Chen; MuhammadTahir Aleem; SuHui He; Yang Yang; TianYuan Zhou; JunLong Liu; JianXun Luo; RuoFeng Yan; LiXin Xu; XiaoKai Song; XiangRui Li

doi:10.1016/j.micpath.2021.104835

Histone deacetylase SIR2 in Toxoplasma gondii modulates functions of murine macrophages in vitro and protects mice against acute toxoplasmosis in vivo

Microb Pathog. 2021 May:154:104835. doi: 10.1016/j.micpath.2021.104835. Epub 2021 Mar 14.

Authors

ZhengQing Yu¹, SiYing Chen², MuhammadTahir Aleem³, SuHui He⁴, Yang Yang⁵, TianYuan Zhou⁶, JunLong Liu⁷, JianXun Luo⁸, RuoFeng Yan⁹, LiXin Xu¹⁰, XiaoKai Song¹¹, XiangRui Li¹²

Affiliations

¹ MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: 2018207044@njau.edu.cn.
² MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: 2018107047@njau.edu.cn.
³ MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: 2018207076@njau.edu.cn.
⁴ MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: 17117116@njau.edu.cn.
⁵ MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: 17117316@njau.edu.cn.
⁶ MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: 2018107049@njau.edu.cn.
⁷ State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, PR China. Electronic address: liujunlong@caas.cn.
⁸ State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, PR China. Electronic address: luojianxun@caas.cn.
⁹ MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: yanruofeng@njau.edu.cn.
¹⁰ MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: xulixin@njau.edu.cn.
¹¹ MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: songxiaokai@njau.edu.cn.
¹² MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China. Electronic address: lixiangrui@njau.edu.cn.

PMID: 33731306
DOI: 10.1016/j.micpath.2021.104835

Abstract

Silent information regulator 2 (SIR2) in histone deacetylase (HDAC) is particularly conserved and widely expressed in all eukaryotic cells. HDAC is a crucial post-translational modification protein regulating gene expression. In the present study, a Toxoplasma gondii (T. gondii) silent information regulator 2 (TgSIR2) gene in HDAC was cloned and the modulation effects of recombinant TgSIR2 (rTgSIR2) on murine Ana-1 macrophages were characterized in vitro. The results indicated that rTgSIR2 had a good capacity to eliminate T. gondii by promoting proliferation, apoptosis, and phagocytosis, and modulating the secretion of nitric oxide (NO), pro-inflammatory cytokines, and anti-inflammatory cytokines. In in vivo experiments, animals were immunized with recombinant TgSIR2, followed by a lethal dose of T. gondii RH strain challenge 14 days after the second immunization. As compared to the blank and control group, the animals immunized with rTgSIR2 could generate specific humoral responses, as demonstrated by the significantly high titers of total IgG and subclasses IgG1 and IgG2a. Significant increases of IFN-γ, IL-4, and IL-10 were seen, while no significant changes were detected in IL-17. The percentage of CD4⁺ and CD8⁺ T lymphocytes in animals immunized with rTgSIR2 significantly increased. A significantly long survival time was also observed in animals vaccinated with rTgSIR2 14 days after the last immunization. All these results clearly indicate that rTgSIR2 played an essential role in modulating host macrophages and offered the potential to develop a therapeutic strategy against T. gondii.

Keywords: Histone deacetylase; Murine macrophage; Protective immunity; Silent information regulator 2 (SIR2); Toxoplasma gondii.

MeSH terms

Animals
Antibodies, Protozoan
Cytokines
Histone Deacetylases / genetics
Macrophages
Mice
Mice, Inbred BALB C
Protozoan Proteins / genetics
Sirtuin 2
Toxoplasma*
Toxoplasmosis, Animal* / prevention & control
Vaccines, DNA*

Substances

Antibodies, Protozoan
Cytokines
Protozoan Proteins
Vaccines, DNA
Sirtuin 2
Histone Deacetylases