DNA damage-regulated autophagy modulator 1 (DRAM1)-induced lipophagy facilitates Toxoplasma gondii nutrient acquisition and infection

Abstract

Autophagy is a catabolic process that responds to various environmental stresses, such as nutrient deficiency and intracellular pathogen infection. Toxoplasma gondii is an intracellular parasite that acquires nutrients from the host cells for its proliferation; however, the molecular mechanisms of T. gondii parasites’ nutritional acquisition and metabolism are not fully understood. Here, we found that T. gondii type I RH strain induced host cell autophagy for nutrient acquisition and growth. T. gondii RH strain infection induced DNA damage-regulated autophagy modulator 1 (DRAM1) expression in host cells, and mechanistic analyses suggest an involvement of the IL-33-MyD88-p38/NF-κB signaling pathway in this process. DRAM1 knockdown decreased T. gondii parasite growth, while DRAM1 overexpression increased T. gondii parasite growth by hyperactivating autophagy, especially lipophagy, to provide fatty acids for T. gondii proliferation, which led to increased tissue pathology. This study identified DRAM1 as a critical molecule in regulating type I T. gondii-induced lipophagy, parasite proliferation, and liver pathology in mice. The results provide crucial insights into how T. gondii leverages host autophagy for its gain and identify a target for potential disease management, which may offer new avenues for developing novel drugs against this parasite.