Toxoplasma gondii (Toxoplasma) causes an acute infection characterized by replicating tachyzoites that eventually develops into a chronic infection characterized by persisting bradyzoite stage Toxoplasma cysts in the brain and central nervous system. Chronic Toxoplasma infection affects ~30% of the United States population and during immune deficiency cysts reactivate and cause a severe Toxoplasmic encephalitis. There are currently no drugs or therapies that are effective at preventing cyst development or eliminating cysts in chronically infected individuals. The biology underpinning Toxoplasma cyst development, reactivation, and host immune control of acute and chronic infection is still poorly understood. From current evidence and preliminary data, we hypothesize that iron availability regulates parasite differentiation, cyst reactivation, and the effectiveness of the CD8+ T cell immune response in controlling acute infection and in preventing cyst reactivation.
In Aim 1 we will investigate the role of iron sensing by the Toxoplasma Iron Regulatory Protein in differentiation and cyst reactivation.
In Aim 2 we will investigate the role of iron availability in the development of CD8+ T cell mediated immunity and in the control of chronic cysts by CD8+ T cells. These two specific aims will test our novel hypothesis that iron regulates parasite stage differentiation and host immunity to acute and chronic infection. These high impact experiments are expected to define key iron regulated mechanisms that act on the parasite as well as the host to control differentiation, reactivation, and host immune control of infection. These studies address significant current gaps in knowledge that are major barriers to progress in the field.
The proposed studies are relevant to public health because dissecting how iron is involved in development of chronic Toxoplasma gondii infection and reactivation of cysts can improve therapies to control this infection. This is relevant to the NIH's mission that pertains to reducing illness and morbidity associated with infection.
