Chagas disease is a zoonotic pathology, caused by the protozoan parasite Trypanosoma cruzi. Endemic en Latin America, it is one of the leading causes of congestive heart failure in the world. Historically associated with poverty in rural areas, immigration and relocation of the vectors are changing the epidemiology of the disease, as evidenced by a substantial increase in the number of cases in the U.S. Treatment is restricted to nifurtimox and benznidazole. Both drugs are relatively toxic, have limited efficacy and are not approved by the FDA. The study of mechanisms of sensing, adaptation and survival of the parasite is important for the identification of selective drug targets that can lead to the elimination of the parasite without affecting the host. During its transformation into different life stages, T. cruzi finds extreme fluctuations in environmental conditions to which it must adapt in order to survive. Mechanosensitive channels are ion channels able to detect changes in the tension of the membranes and are activated by stretch of the lipid bilayer. They are considered the primary sensors of osmotic changes in a multiplicity of cells and organisms, triggering signaling pathways that drive osmoregulation. Although T. cruzi has a robust compensatory response under osmotic stress, the identity of the molecules detecting changes and eliciting adaptive responses in the parasites is still unknown. We have identified a channel with structural features shared by small conductance mechano-sensitive channels (TcMcS) and we propose that mechanosensitive channels with homology to bacterial channels play an important role in sensing and adaptation to environmental conditions in T. cruzi, determining the success of the host cell invasion and survival of the parasite. Analysis of T. cruzi mechanosensitive channels expression profiles and localization, complemented with electrophysiological studies will shed light about the mechanism of activation and modulation of these proteins. Genetic manipulation of the level of expression and phenotypic analysis in vivo will demonstrate the physiological role of TcMcS channels in the parasite and will help to establish their potential as therapeutic targets.
|Effective start/end date||07/01/2016 → 06/30/2018|