The chief long-term objective of my research is to understand the immunopathology of chronic intracellular infections. Infection with Trypanosoma cruzi, which causes Changas' disease, is an excellent model for chronic intracellular infections and for the study of an infection that leads to autoimmunity. A 160 kD T. cruzi antigen (F1-160), which is found on the surface overlying the flagellum, has been characterized by expression of T. cruzi genomic DNA1. It was found that F1-160 mimics epitopes of a nervous tissue protein, found in the neuronal cells of myenteric plexi and other elements of the nervous system. Inflammatory destruction of the myenteric plexi leads to megagastrointestinal manifestations characteristic of chronic Chagas' disease. Thus, F1-160 is a candidate for causing autoimmune destruction by molecular mimicry of critical organ proteins.
The specific aims of this proposal are to study the hypotheses that: 1) autoimmunity in chronic Chagas' disease is caused by antigenic mimicry and loss of tolerance; 2) the T. cruzi F1-160 antigen, because of its antigenic mimicry, leads to the autoimmune destruction of critical nervous tissue; 3) T cells orchestrate the autoimmune attack caused by F1-160; and 4) analysis of the immune response during acute infection will give insights into: how T. cruzi establishes a chronic infection, how immunopathogenesis contributes to acute disease manifestations, and how acute infection leads to loss of tolerance and eventual autoimmunity. The secondary objective of the proposal will be to study the molecular expression of F1-160 to understand the mechanisms by which T. cruzi expresses surface proteins. The experimental plan to accomplish the specific aims are: 1) to characterize the epitope(s) of F1-160 that mimic mammalian nervous tissues; 2) to characterize the F1-160 cross-reactive protein in normal mammalian nervous tissues (nxF1-160); 3) to study cellular immunity to F1-160 and nxF1-160; 4) to analyze the molecular expression of F1-160; and 5) to analyze the acute human immune response to T. cruzi infection.
| Van Voorhis, W C; Pham, V T; De Vos, T (1995) The FL-160 genes of Trypanosoma cruzi are dispersed on multiple chromosomes. Exp Parasitol 80:578-82 |
| Van Voorhis, W C; Barrett, L; Koelling, R et al. (1993) FL-160 proteins of Trypanosoma cruzi are expressed from a multigene family and contain two distinct epitopes that mimic nervous tissues. J Exp Med 178:681-94 |
| Cetron, M S; Basilio, F P; Moraes, A P et al. (1993) Humoral and cellular immune response of adults from northeastern Brazil with chronic Trypanosoma cruzi infection: depressed cellular immune response to T. cruzi antigen among Chagas' disease patients with symptomatic versus indeterminate infection. Am J Trop Med Hyg 49:370-82 |
