The Impact of Host Arginine Metabolism on Toxoplasma gondii Infection and Growth Dynamics.

Arginase enzymes play a crucial role in cellular homeostasis across all Domains of life. In vertebrates, arginase isoform I (Arg1) drives the urea cycle in the liver, and arginase isoform II (Arg2) systemically contributes to the biosynthesis of essential molecules such as polyamines. While these isoenzymes share the same function, their distinguishing roles in various metabolic and immunologic pathways remain undefined. Arg1 is well-characterized as an essential enzyme in mammalian homeostasis. Literature suggests that Arg2, though non-essential, may modulate the host response to infection via unknown mechanisms. Toxoplasma gondii is an intracellular eukaryotic parasite that uniquely lacks both arginases and other essential enzymes in arginine metabolism. Consequently, T. gondii relies on siphoning arginine and downstream metabolites, including polyamines, from the host for its survival and replication. In investigating the role of arginase 2 in T. gondii infection, we discovered a significant growth defect of T. gondii in tissue culture fibroblasts treated with the arginase inhibitor, norNOHA. Interestingly, when attempting to rescue the growth of the parasite by supplementing polyamines, a compounding defect in T. gondii growth is observed. Finally, Arg2 knockout mice are more likely to survive T. gondii infection compared to wildtype mice. These results reinforce our hypothesis suggesting that Arg2 contributes to T. gondii infection both in vitro and in vivo. Future studies will utilize metabolomics and transcriptomics to define the role of Arg2 in T. gondii infection to offer a broader context in understanding complex interactions for both the host and parasite. The aim of this study is to identify potential drug targets in the early stages of T. gondii infection.