Exploiting the cAMP pathway in Chagas Disease Therapy

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DESCRIPTION (provided by applicant): This Fogarty International Research Collaboration Award (FIRCA) application, based on parent grant R01 CA071649-11 (Principal Investigator Altschuler, Daniel), was designed to expand the research capacity of the foreign scientist (Dr. Martin Edreira) and institution (Universidad de Buenos Aires, Buenos Aires, Argentina), exploiting the cAMP signaling pathway in search of a potential target to a global public health illness, i.e. Chagas disease. Chagas disease is a life-threatening illness caused by the protozoan parasite Trypanosoma cruzi. Endemic to poor rural areas of South America, with an infected population estimated in 10 million and an alarming 25,000 deaths per year, its impact is becoming global due to migration to developed countries; estimates indicate that around 300,000 infected migrants currently live in the US. No vaccines are available, and drugs introduced in the early 1970's, i.e. nifurtimox and benznidazole, represent the only currently available options for treatment. These anti-parasitic drugs, however, show limited efficacy and high toxicity. Thus, the development of novel alternative treatments is urgently needed. Roles for cAMP-dependent signaling pathways, both in the parasite and the host mammalian cell, are well established as modulators of T. cruzi's cell cycle and its ability to invade the host. Although much attention is focused on the putative machinery involved in synthesis (i.e. cyclase) and degradation (i.e. phosphodiesterase) of cAMP, the role of potential new cAMP effector pathways is currently unknown. The goal of the parental grant was the identification and characterization of new PKA-independent cAMP effector pathways in mammalian cells, as well as the development of specific reagents for their analysis. The general hypothesis to be tested in this application is that, similarly to mammalian cells, multiple cAMP effector pathways might play significant roles in the pathogenic mechanisms used by this human parasite. Two specific aims are proposed to approach this: Sp. Aim 1: To identify and characterize new cAMP effectors in T. cruzi, and Sp. Aim 2: To determine the role of specific mammalian cAMP effectors during host invasion. Successful completion of the proposed aims has the potential to uncover new aspects of cAMP biology and to provide new insights into the mechanisms of pathogenesis involved in Chagas disease. Although most of the studies will be performed by Dr. Edreira at the Universidad of Buenos Aires in Argentina, all the tools generated or currently in process from the parent grant at the University of Pittsburgh will be readily available for Dr. Edreira's research. The close collaboration between laboratories with strong expertise in cAMP biology and Chagas research should provide a productive environment that will potentially advance the field of T. cruzi biology, its interaction with the host cell and holds promise of identifying new and unique target/s for future intervention. PUBLIC HEALTH RELEVANCE: Chagas is a potentially life-threatening disease caused by the protozoan parasite, Trypanosoma cruzi. Endemic to the Americas, it represents a serious health threat among people living in poor rural populations in Latin America. Available anti-parasitic drugs have limited effectiveness and are highly toxic. For this reason, there is an urgent need for new treatments, implying the identification of new potential targets and the design of novel drugs for anti-trypanosomal therapy. cAMP pathways, involved in T. cruzi proliferation, differentiation and invasion, are essential for the parasite and could be targets for new drugs. The overall aim of the application focused on the characterization of effector interactions within the cAMP pathway involved in Trypanosoma cruzi biology and in host cell during invasion, in order, to identify specific key players to be use as targets for drug design. The studies proposed should provide new insights into cAMP-dependent signaling events. Unraveling the mechanisms underlying these new interactions might provide insights into the rational design of new specific inhibitors with effector pathway selectivity that might have implications in the development of new therapies for Chagas disease.