leupeptins and Chagas-Disease

Death receptor-mediated host cell apoptosis, a defense strategy for elimination by the immune system of parasite-infected cells, is inhibited by Trypanosoma cruzi, the causative agent of Chagas' disease. It has previously been reported by us that, in infected cells, T. cruzi upregulates and exploits cFLIP(L), a mammalian inhibitor of death receptor signaling. Here it is shown that ubiquitination of cFLIP(L,) leading to proteasomal degradation, is inhibited in parasite-infected cells. The extent of expression of Itch, a protein thought to be an ubiquitin ligase for cFLIP(L), was found to be equivalent in T. cruzi-infected and in uninfected cells. However, co-immunoprecipitation analysis showed that the interaction between cFLIP(L) and Itch is strongly inhibited in T. cruzi-infected cells. This unique parasite strategy, which has not been reported in any other pathogen-infected cells, may allow the host cell to accumulate cFLIP(L), eventually resulting in the inhibition of apoptosis of T. cruzi-infected cells.

Topics: Animals; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Chagas Disease; Cysteine Proteinase Inhibitors; HeLa Cells; Humans; Immunoprecipitation; Leupeptins; Proteasome Inhibitors; Repressor Proteins; Trypanosoma cruzi; Ubiquitin-Protein Ligases; Ubiquitination