Monday, May 6, 2024
5/6/2024
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. Our laboratory has been working on the rational search for chemotherapeutic treatments for Chagas disease that can selectively target the parasite without compromising human cells. 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. 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 usually 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 hyposmotic and hyperosmotic conditions, 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 have identified the presence and expression of a channel with structural features shared by small conductance mechanosensitive channels (TcMcS). TcMcS blockage by genetic and pharmacological methods affects the osmoregulatory capacity of the cells. 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 establish their potential as therapeutic targets.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
