Iron stress affects the survival of Toxoplasma gondii

Abstract Background Iron possesses redox abilities and plays a crucial role in in biosynthesis, energy metabolism, and other biological processes. It represents an indispensable nutrient for the survival of Toxoplasma gondii. In response to Toxoplasma-infection, host cells employ a defensive strategy referred to as "nutritional immunity" to restrict the availability of iron, thus impeding T. gondii from obtaining sufficient amounts of this vital element. The present research aims to examine the impact of iron stress on T. gondii, including iron deficiency and iron overload, and to explore the feasibility of disturbing the iron homeostasis as a potential treatment for toxoplasmosis. Methods An iron-deficient environment was induced by supplementing the culture medium with the permeable iron chelator, deferoxamine mesylate (DFO), while ammonium iron(II) sulfate was utilized as an iron supplement to establish an iron overload environment. Experiments were conducted to assess the impact of different iron levels on T. gondii's proliferation ability, invasion ability, escape ability, and plaque formation, Additionally, the redox ability of T. gondii under varying iron stress conditions was examined. Transcriptome analysis was employed to investigate the differential gene expression of T. gondii under iron deficiency and iron overload. Lastly, iron chelation therapy and iron supplementation therapy were administered to mice infected with T. gondii to assess the potential of targeting iron homeostasis disruption for the treatment of toxoplasmosis. Results Iron supplementation and the iron chelating agent significantly influence the growth of T. gondii. Low iron stress inhibits the proliferation of T. gondii and greatly reduces plaque formation, whereas high iron stress increases the invasion ability while significantly reducing proliferation. Altered iron levels perturb the redox capacity of T. gondii, resulting in a substantial increase in oxidation products (GSSG and MDA), reactive oxygen species (ROS), and superoxide anions under high iron stress. Under iron deficiency, specific genes pertaining to bradyzoites are up-regulated, thereby facilitating the conversion of tachyzoites to bradyzoites in the Pru strain. Conversely, under iron overload, a significant up-regulation of surface protein genes in T. gondii occurs, leading to an enhanced adhesion ability. Notably, the administration of iron supplements and iron chelating agents has no discernible effect on the mortality rates of Toxoplasma-infected mice. Nevertheless, mice infected with T. gondii exhibit significant weight loss and aggravated symptoms following iron supplementation therapy. Conclusions This study unequivocally confirms the essentiality of iron as a nutrient for T. gondii survival. Iron stress, including iron deficiency and iron overload, affects the growth of T. gondii.