High resistance to Toxoplasmagondii infection in inducible nitric oxide synthase knockout rats

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.