The role of host amino acid metabolism in behavioral changes during latent toxoplasmosis

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Toxoplasmosis is an opportunistic disease caused by the obligate intracellular parasite Toxoplasma gondii. This parasite has been infected nearly 2 billion people globally. In healthy individuals, Toxoplasma infection is usually asymptomatic or it presents as mild flu-like symptoms, as the immune system effectively keeps the replicative forms (tachyzoites) from causing illness. However, by converting into latent forms, Toxoplasma forms tissue cysts in the brain and heart that persist for a lifetime. Toxoplasma tissue cysts are surrounded by a thick wall which protects the parasites to available drugs and host immune response. Bradyzoites, the latent forms found in tissue cysts, sense the environment and can be released from the cysts and transformed into tachyzoites, which results in reactivation of the disease. This frequently occurs in HIV/AIDS patients, and it causes brain lesions that can be life-threatening. In healthy individuals, there is a correlation between chronic toxoplasmosis and neurocognitive impairment, as well as mental and neurological disorders. We previously demonstrated that neuroinflammation is one of the major factors that contribute to behavioral changes in Toxoplasma-infected mice; this was recently confirmed by another study that found that several amino acid related genes are dysregulated in the brains of infected mice, contributing to behavioral alterations and neuroinflammation. Auxotrophic for several nutrients Toxoplasma acquires amino acids from the host to establish infection, which affects the host cell metabolism and amino acid availability. We recently demonstrated that Toxoplasma depletes arginine in infected cells leading to host metabolic changes resulting in higher expression of host cationic amino acid transporter-1 (CAT1) regulated by GCN2. Toxoplasma infection induces not only CAT1 expression but also increases the arginine transporter activity, elevating the arginine levels of infected cells. While we have made progress in understanding the role of arginine during Toxoplasma acute infection, the role of this and other host amino acid availability during chronic toxoplasmosis has been frustratingly mysterious. Our preliminary findings support our working hypothesis that Toxoplasma modulates host amino acid pathways to establish chronic infection. This proposal will test the hypothesis that two-host amino acid metabolism pathways, GCN2 and mTORC1, mediate parasite persistence in the brain. Our experimental plan consists of two independent aims that will elucidate the role of amino acid metabolism during Toxoplasma infection in the brain and how amino acid availability contribute to behavioral changes in chronically infected mice. Aim 1 will determine the role of host amino acid levels during development of Toxoplasma tissue cysts in mice. Aim 2 will elucidate the role of GCN2 and mTORC1 pathways in neurological alterations during Toxoplasma infection. Resolving the mechanism underlying this observation will provide much needed insight into how the parasite causes neurological alterations putting us in a better position to develop novel therapies to treat Toxoplasma in patients.