The phytochemical arbutin exerts potent anti-Toxoplasma effects through activation of cell-autonomous defense mechanisms while attenuating inflammation.

BACKGROUND: Plant-derived natural products have emerged as promising candidates for developing novel anti-toxoplasmosis drugs. This study aimed to elucidate the role and mechanism of the phytochemical arbutin in the control of T. gondii infection. METHODOLOGY/PRINCIPAL FINDINGS: The effect of arbutin on T. gondii infection and host inflammatory response was evaluated both in vitro and in vivo. RNA-seq was performed on mouse bone marrow-derived macrophage samples to identify potential arbutin-related biological processes and molecular targets that control T. gondii infection. These targets were further confirmed using target-specific activators or inhibitors. Our data indicated that arbutin has dual therapeutic effects against T. gondii infection through concurrently controlling parasite growth and mitigating infection-induced inflammation. Mechanistically, arbutin mediates restriction of intracellular labile iron pool in both immune and non-immune cells, thereby depriving the parasite of essential metal nutrients. In addition, in macrophages, arbutin not only inhibits infection-induced inflammatory response but also upregulates the expression of heme degrading enzyme heme oxygenase-1, which facilitates biliverdin production. Our data further demonstrated that biliverdin exhibits anti-T. gondii effector function. Furthermore, arbutin is also effective in reducing infection-related mortality in immunocompromised mice. CONCLUSIONS/SIGNIFICANCE: Our data highlight arbutin's potential therapeutic value in fighting against acute hyperinflammatory phase of Toxoplasmosis even in immunocompromised host but also its limitation in establishing long-term immunity. Our study further suggests a potential direction for further development of effective drugs to prevent and treat toxoplasmosis by pharmacologically enhancing cell-autonomous defense mechanisms while suppressing inflammatory response.