The chief long-term objective is to understand the immunopathology of chronic intracellular infections. Infection with Trypanosoma cruzi, which causes Chagas' 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 (Fl-160), which is found on the surface overlying the flagellum, has been characterized by expression of T. cruzi genomic DNA. It was found that Fl-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 mega-gastrointestinal manifestations characteristic of chronic Chagas' disease. Thus, Fl-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 Fl-160 antigen, because of its antigenic mimicry of nervous tissues leads to the autoimmune destruction of critical nervous tissue, observed in chronic Chagas' disease; 3) T cells orchestrate the autoimmune attack caused by Fl-160; and 4) analysis of the immune response during acute infection will give insight 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 other objective of the proposal is the study of the molecular expression of Fl-160.
The specific aim of this research is based on the hypothesis that understanding the molecular expression of Fl-160 will give insight into the mechanisms T. cruzi uses for the expression of surface proteins. The experimental plan to accomplish the specific aims are: 1) to characterize the epitope(s) of Fl-160 that mimic mammalian nervous tissues; 2) to characterize the Fl-160 cross-reactive protein in normal mammalian nervous tissues (nxFl-160); 3) to study cellular immunity to Fl-160 and nxFl-l6O; 4) to analyze the molecular expression of Fl-160; and 5) to analyze the acute human 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 |
| Kahn, S; Kahn, M; van Voorhis, W C et al. (1993) SA85-1 proteins of Trypanosoma cruzi lack sialidase activity. Mol Biochem Parasitol 60:149-52 |
