Viernes 29 de Septiembre
Resumen del seminario
Dr. Fernando Sánchez-Valdéz
Instituto de Patología Experimental
"The basis of treatment failure in T. cruzi infections: Resistant strains, differential tropisms or parasite dormancy".
Benznidazole (BZ), the primary drug used to treat Chagas disease, fails to provide parasitological cure in the majority of cases, despite long treatment times (up to 60 days). In a number of infections, drug treatment failures have been linked to the presence of subpopulations of pathogens that become physiologically inactive or dormant. These so-called persister cells may be stochastically generated in pathogen populations and have been hypothesized to serve as a survival mechanism against possible catastrophic events that could eliminate an entire metabolically active population. In our analysis of persisting parasites in mice with chronic T. cruzi infection, we consistently observed the existence of rare amastigotes not undergoing active proliferation, as assessed by the incorporation of the thymidine analog 5-ethynyl-2´-deoxyuridine (EdU) into amastigote DNA. Quiescent amastigotes were also evident in vitro even after prolonged incubation with EdU (72hr). TUNEL assays determine that these dormant parasites were not dead within host cells. Incorporation of EdU into DNA can impact DNA replication, so we used labeling with fluorescent dyes as an alternative protocol to monitor amastigote replication. We not only confirmed in vivo and in vitro results, but also found that non-proliferating amastigotes were able to resume proliferation: differentiate to trypomastigotes, infect new host cells, replicate and generate again a progeny of dormant forms. Remarkably, the screening of adipose tissue from infected mice treated with BZ revealed the resistance capacity of dormant parasites. Replicating amastigotes are sensitive to drug and could not been detected. The cause of this arrest and the link between these parasites and drug treatment failures in vivo will be the subject of future studies.
Horario: 9 hs.
Lugar: Facultad de Ciencias de la Salud, 2º piso. UNSa.
Se ruega puntualidad
Enlaces relacionados: SANCHEZ VALDEZ Fernando Javier