High resistance to Toxoplasma gondii infection in inducible nitric oxide synthase knockout rats

Zhen-Jie Wang; Shao-Meng Yu; Jiang-Mei Gao; Peng Zhang; Geoff Hide; Masahiro Yamamoto; De-Hua Lai; Zhao-Rong Lun

doi:10.1016/j.isci.2021.103280

High resistance to Toxoplasma gondii infection in inducible nitric oxide synthase knockout rats

iScience. 2021 Oct 15;24(11):103280. doi: 10.1016/j.isci.2021.103280. eCollection 2021 Nov 19.

Authors

Zhen-Jie Wang¹, Shao-Meng Yu¹, Jiang-Mei Gao², Peng Zhang¹, Geoff Hide³, Masahiro Yamamoto⁴, De-Hua Lai¹, Zhao-Rong Lun^{1

2

3}

Affiliations

¹ Guangdong Provincial Key Laboratory of Aquatic Economic Animals, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, The People's Republic of China.
² Department of Parasitology, Key Laboratory of Tropical Disease Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, The People's Republic of China.
³ Biomedical Research Centre, School of Science, Engineering and Environment, University of Salford, Salford M5 4WT, UK.
⁴ Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.

Abstract

Nitric oxide (NO) is an important immune molecule that acts against extracellular and intracellular pathogens in most hosts. However, after the knockout of inducible nitric oxide synthase (iNOS ^-/-) in Sprague Dawley (SD) rats, these iNOS ^-/- rats were found to be completely resistant to Toxoplasma gondii infection. Once the iNOS ^-/- rat peritoneal macrophages (PMs) were infected with T. gondii, they produced high levels of reactive oxygen species (ROS) triggered by GRA43 secreted by T. gondii, which damaged the parasitophorous vacuole membrane and PM mitochondrial membranes within a few hours post-infection. Further evidence indicated that the high levels of ROS caused mitochondrial superoxide dismutase 2 depletion and induced PM pyroptosis and cell death. This discovery of complete resistance to T. gondii infection, in the iNOS ^-/--SD rat, demonstrates a strong link between NO and ROS in immunity to T. gondii infection and showcases a potentially novel and effective backup innate immunity system.

Keywords: Immunology; Microbiology; Parasitology.