The primary goal of the proposed investigation is to establish an animal model of Toxoplasma encephalitis (TE) in simian immunodeficiency virus (SIV)-infected rhesus macaques. Infection with Toxoplasma gondii is now recognized as the most frequent cause of focal central nervous system disease in patients with AIDS. Individuals with serologic evidence of prior exposure to Toxoplasma are at particular risk of developing TE during HIV infection, presumably from reactivation of latent disease. Details of the pathogenesis of this disease in the immunocompromised host are unclear. We propose to study the clinical progression and pathology of toxoplasmosis in immunocompetent and immunodeficient Macaca mulatta using the Simian Immunodeficiency Virus macaque model currently being maintained at the Regional Primate Research Center at the University of Washington. Six animals will initially be infected with RH strain Toxoplasma and followed clinically and serologically for establishment of acute and chronic phases of the disease. Responses of macaques to induced toxoplasmosis have previously been shown to parallel those of man, with the development of latent infection occurring after 1-2 months. Following development of latency, 4 animals will subsequently be infected with SIV and monitored for that disease, and for evidence of Toxoplasma reactivation. Upon clinical evidence of reactivation, animals will be euthanized and studied using routine postmortem and immunohistochemical techniques. Histologic changes will be compared to those present in animals infected with either Toxoplasma or SIV alone. Because death in SIV-infected macaques usually occurs 9 to 18 months following exposure, we anticipate completing these experiments over a two year period. Future studies utilizing this primate model will allow us to 1) examine in detail the pathogenesis of toxoplasmosis in the immunocompromised host; 2) evaluate new anti-Toxoplasma therapies; and 3) develop new diagnostic assays.
| McGonigle, Sharon; Beall, Melissa J; Pearce, Edward J (2002) Eukaryotic initiation factor 2 alpha subunit associates with TGF beta receptors and 14-3-3 epsilon and acts as a modulator of the TGF beta response. Biochemistry 41:579-87 |
| Beall, M J; Pearce, E J (2001) Human transforming growth factor-beta activates a receptor serine/threonine kinase from the intravascular parasite Schistosoma mansoni. J Biol Chem 276:31613-9 |
