Exploiting Host Endoplasmic Reticulum: Toxoplasma gondii's Strategy for Amino Acid Acquisition and Brain Persistence

Toxoplasma gondii, a widespread parasite, has the ability to infect nearly any nucleated cell in warm-blooded vertebrates. Approximately 2 billion people worldwide are estimated to have been infected by this pathogen. Although most healthy individuals can effectively control parasite replication, certain parasites may evade the immune response, establishing cysts in the brain that resist both immune reactions and available drugs. For its chronic persistence in the brain, the parasite relies on host cells' nutrients, particularly amino acids and lipids. The current recommended therapy for toxoplasmosis has severe adverse effects and targets only acute forms of the parasite. Therefore, understanding how latent parasites persist in the brain is crucial for identifying potential drug targets against chronic forms. While shielded within parasitophorous vacuoles (PVs) or cysts, Toxoplasma has developed mechanisms to exploit the host endoplasmic reticulum (ER) metabolism, acquiring amino acids to sustain brain persistence, resulting in host neurological alterations. In this study, we demonstrate that Toxoplasma gondii disrupts host ER homeostasis, leading to unfolded protein accumulation in the host ER lumen. In response to this stress, the host activates an autophagic pathway called ER-phagy to alleviate the stress. Remarkably, by restricting amino acids in cell culture or during latent infection in mice, we successfully decreased the persistence of latent forms and restored behavioral changes in mice caused by the infection. Our findings unveil the underlying mechanisms employed by Toxoplasma gondii to exploit host ER and lysosomal pathways, enhancing nutrient levels during infection. These insights provide new strategies for the treatment of toxoplasmosis.