Prokineticin receptor 1 and 2 (PKR1 and PKR2) are two G-protein coupled receptors (G-PCRs) which share 85% sequence identity, with the major differences concentrated in the amino and carboxyl-terminal regions of the molecules. Although both PKR1 and PKR2 are co-expressed in various tissues including brain, PKR1 is mainly expressed in peripheral tissues, while PKR2 is widely expressed in central nervous system. In rodents, prokineticin receptors (PKRs) are activated by small-secreted cysteine-rich peptides, prokineticin 1 and 2 (PK1 and PK2), and regulates a variety of biological processes including angiogenesis, neurogenesis, circadian rhythm, haematopoiesis, immune response or nociception.
Chagas disease is caused by the intracellular protozoan parasite Trypanosoma cruzi (T. cruzi) and infects >10 million people in Latin America. Although development of improved antiparasitic drugs is considered a priority, there have been no significant treatment advances in the past 40 years.
Recently, the GGIALAG sequence present in PKR2 was described as a new T. cruzi receptor for the Tc85 group of glycoproteins belonging to the gp85/TS superfamily and involved in cellular invasion of mammalian hosts.
Based on these considerations the project aims to analyse these host-parasite molecular complexes. Understanding the molecular details of how T. cruzi infects human's cells is an important step towards the development of new drugs for this disease.
Chagas disease, a chronic systemic parasitosis caused by the protozoon Trypanosoma cruzi (T. cruzi), is the first cause of cardiac morbidity and mortality in countries of Latin America and the largest parasitic disease burden in the continent, now spreading worldwide due to international migrations[1, 2]. The parasite can be naturally transmitted by insects [3, 4], but it can also be transmitted orally by the ingestion of contaminated food, transfusions or transplants of contaminated blood/organs and congenitally from infected mothers to newborns [4, 5]. Unfortunately, due to interactions complexity between parasite and immune system of its mammalian hosts an effective prophylactic vaccine has yet to be developed [6]. Antiparasitic therapy has proven efficacy in clearing T. cruzi infection in acute, congenital and early chronic disease [7, 8, 9], and although there is a trend to offer antiparasitic therapy to chronically infected adults [10], the efficacy of this moderately toxic and poorly tolerated treatment in this stage of the disease remains to be fully evaluated.
In a recent paper the prokineticin receptor 2 (PKR2) has been suggested as potential new T. cruzi receptor in mammalian cells [11]. PKR2 is a G protein coupled receptor (G-PCR) present in the brain, neutrophils, peripheral organs and in fenestrated endothelial cells of the heart, and plays an important role in inflammation and in modulation of immune responses [12, 13].
Tc85, a group of glycoproteins present on the surface of the infective stages of the T. cruzi and described as first molecules involved in parasite adhesion to the host cell, bind GGIALAG sequence present in PKR2. Moreover, a strong inhibition of host cell invasion by T. cruzi was reported when anti-PKR2 antibody was used [11, 14].
This project aims investigate and understand the molecular mechanisms involved in parasite host interactions and which are the signaling pathways activated by Tc85 glycoproteins when bind PKR2. All these data are identifying PKR2 as novel potential therapeutic targets for the development of novel strategies to control Trypanosome invasion, infection and its associated pathologies.
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