AIDS associated Toxoplasma encephalitis

ABSTRACT: Toxoplasma gondii remains an important cause of neurologic infection in people living with HIV/AIDS (PLWHA) and continues to cause high morbidity and mortality in PLWHA. The predilection of this protozoan for the central nervous system causing necrotizing encephalitis underlies its major presentation in PLWHA. Since it can be transmitted by food or water T. gondii is also classified as a category B NIH priority pathogen. The ability of this opportunistic pathogen to cause latent infection in the central nervous system with subsequent reactivation encephalitis, due to the cell mediated immune defects seen in HIV infection, represents its major risk to PLWHA. The estimated incidence of Toxoplasma encephalitis in the combination antiretroviral therapy (cART) era is ∼4000 cases per year in the United States. T. gondii remains a common infection in patients with persistent immune suppression (i.e., CD4 count under 100) and a presenting opportunistic infection in patients not on cART. Following initial infection T. gondii disseminates as its rapidly proliferating tachyzoite stage which then differentiates into the slowly replicating bradyzoite stage that is found in tissue cysts in the central nervous system. These tissue cysts usually persist for the life of the host; however, reactivation of this latent infection in PLWHA results in encephalitis. Tissue cysts, and the cyst wall, are essential for the development of latent infection, survival of T. gondii during latency, and reactivation of this opportunistic pathogen in PLWHA leading to Toxoplasma encephalitis. Several lines of evidence suggest that bradyzoite differentiation is stress mediated and that the cyst wall (a modified parasitophorous vacuole membrane) is made up of many stage specific proteins and glycoproteins. Understanding the formation and composition of the cyst wall will inform strategies (e.g., vaccine development and therapeutic agents) to eliminate latency and prevent AIDS associated Toxoplasma encephalitis. We have developed techniques to characterize this structure and have found several T. gondii cyst wall proteins that have been shown to prevent latent infection when used as vaccine antigens. We have also identified CST1, which is a critical component of the cyst wall and plays a role in the assembly of this structure. We now propose an integrated approach employing state of the art proteomic, immunologic, and genetic techniques to characterize this critically important structure. An improved understanding of the formation of the cyst wall will provide the basic underpinnings of new strategies to eliminate latent infection thereby preventing AIDS associated Toxoplasma encephalitis.