Characterization of potassium channels in the human parasite Trypanosoma cruzi

Jimenez, Veronica

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 efficac 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. Ion channels are potential targets for selective drugs against a broad range of diseases because they are responsible for essential cellular functions like plasma membrane and mitochondrial membrane potential maintenance, pH regulation, cell proliferation, and adaptation to environmental changes including osmoregulation. During its life cycle, the parasite encounters extreme fluctuations in ionic concentrations, osmolarities and pHs. Previous studies in our laboratory suggested that in T. cruzi, K+ channels are important components of the regulatory mechanisms that maintain the plasma membrane potential, intracellular pH and osmolarity. It has also been demonstrated that trypomastigotes, the infective forms of the parasite, are particularly sensitive to changes in extracellular K+ concentration while epimastigotes and amastigotes are less responsive to this ion. In T. cruzi, we have identified sequences encoding for putative inward rectifier (TcKir) and calcium-activated K+ channels (TcCAKC). They have conserved functional domains, but limited identity with human homologs (<15%) making them potential selective pharmacological targets against the parasite. We propose that ion channels play an important role in sensing and adaptation to environmental conditions in T. cruzi. We propose that different types of K+ channels integrate a homeostatic network that allows the parasite to detect and respond to changes in osmotic and ionic conditions. Fundamental processes like differentiation and invasion can be regulated by modification of the ionic concentrations determining the success of the parasite in infecting new hosts. Analysis of T. cruzi potassium channels expression profiles and localization, complemented with electrophysiological studies will shed light about how these proteins work. Genetic manipulation of the level of expression and phenotypic analysis in vivo will demonstrate the physiological role of potassium channels in the parasite and will help to establish their potential as therapeutic targets. Public Health Relevance: Chagas disease is a tropical pathology, caused by the parasite Trypanosoma cruzi. Endemic in Latin America, it is one of the leading causes of heart disease in the world. Historically associated with poverty in rural areas, immigration and relocation of th insect that transmits the disease are changing the epidemiology, as evidenced by a substantial increase in the number of cases in the US. Only two drugs are available for the treatment of Chagas disease, both of which are relatively toxic and have limited efficacy. We have been working on the rational search for chemotherapeutic alternatives that can selectively target the parasite without compromising human cells. Understanding of the adaptation and survival mechanisms that the parasite uses to cope with environmental changes will contribute to the identification of new therapeutic targets.

Public Health Relevance

Chagas disease is a tropical pathology, caused by the parasite Trypanosoma cruzi. Endemic en Latin America, it is one of the leading causes of heart disease in the world. Historically associated with poverty in rural areas, immigration and relocation of the insect that transmit the disease are changing the epidemiology, as evidenced by a substantial increase in the number of cases in the US. Only two drugs are available for the treatment of Chagas disease, both of which are relatively toxic and have limited efficacy. We have been working on the rational search for chemotherapeutic alternatives that can selectively target the parasite without compromising human cells. Understanding of the adaptation and survival mechanisms that the parasite uses to cope with environmental changes will contribute to the identification of new therapeutic targets. !