Abstract P407: Role Of Cyclic AMP During The Intracellular Infection Cycle Of Trypanosoma Cruzi

Abstract

Trypanosoma cruzi is the causative agent of Chagas disease, a vector-borne disease. In the 1990s the distribution of the vector, a hematophagous triatomine, and consequently the parasite, was from the southeast tropical regions of Mexico to South America. Now, global warming is causing this distribution to expand to northern territories in Mexico, reaching southern parts of US, in which up to 300,000 people are affected. Furthermore, an increase in chronically-infected immigrants to the US makes Chagas disease a matter of Pan-American public health that it should be addressed by all the America countries. Chagas disease manifests clinically as cardiovascular disease, characterized by hypertrophy of heart, esophagus and colon. Congestive heart failure is the main cause of death (58%) in Chagas patients, whereas cardiac arrhythmias and unexpected deaths add another 36%. A major cause of heart pathology in Chagas disease damage is caused by the host immune system, as it attacks chronically infected tissue. Therefore, pathology of the disease is a direct consequence of the ability of the parasite to invade host cells, so it can establish chronic infection. To achieve this, T. cruzi must sense and adapt to the host environment, but the underlying mechanisms are poorly understood. In particular, parasite signaling pathways used to sense and transduce signals from the host environment are most completely unknown. Our lab studies cAMP signaling in trypanosome parasites and several lines of evidence suggest T. cruzi cAMP signaling is important for host cell invasion, differentiation and persistent infection, which in turn underlies heart tissue pathology of Chagas disease. A transcriptome analysis revealed that mRNA of proteins involved in cAMP metabolism, i.e. adenylate cyclases and phosphodiesterases, are either upregulated or downregulated during the intracellular infection cycle. In fact, the phosphodiesterases have flagellar homologs with known cAMP signaling functions in a related parasite. This suggests that cAMP might fluctuate during as T. cruzi invades, differentiates, and multiplies inside the host cells. We have implemented a cAMP FRET sensor to monitor cAMP levels in trypanosomes to understand the role of cAMP in T. cruzi pathogenesis.