Thursday, December 26, 2024
12/26/2024
Abstract Chagas disease is a zoonotic tropical pathology, caused by the protozoan parasite Trypanosoma cruzi. Endemic in 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 US. Treatment is restricted to nifurtimox and benznidazole, both of which are relatively toxic, have limited efficacy and are not approved by the FDA for general use. The study of the 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 cells. During the 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 cation channels able to detect changes in the tension of the membranes and are usually activated by stretch of the lipid bilayer. They are considered the primary sensors of tension changes in a multiplicity of cells and organisms, triggering signaling pathways that drive osmoregulation, shear stress sensing and differentiation. Although T. cruzi has a robust capacity to survive in various environments, the identity of the molecules detecting changes and eliciting adaptive responses in the parasites is still unknown. Previous in silico studies suggest the presence of several putative mechanosensitive channels in T. cruzi. We are focusing our work in two types of proteins: TcMscS, a channel with structural features shared by bacterial small conductance mechanosensitive channels; and Piezo channels, large proteins that regulate functions such as cell volume, shear stress sensing and motility. We propose that mechanically activated channels play an important role in sensing and adaptation to environmental conditions in T. cruzi, determining the success of the host cell invasion and the 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. Additionally, we will explore the activation of signaling pathways linked to the activation of the channels. Genetic manipulation of the level of expression and phenotypic analysis in vivo will demonstrate the physiological role of TcMscS and TcPiezo channels in the parasites and will help establishing their potential as therapeutic targets.
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